EP1829876A1 - Compose tricyclique azote - Google Patents

Compose tricyclique azote Download PDF

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Publication number
EP1829876A1
EP1829876A1 EP05809668A EP05809668A EP1829876A1 EP 1829876 A1 EP1829876 A1 EP 1829876A1 EP 05809668 A EP05809668 A EP 05809668A EP 05809668 A EP05809668 A EP 05809668A EP 1829876 A1 EP1829876 A1 EP 1829876A1
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EP
European Patent Office
Prior art keywords
group
substituted
alkyl group
compound
salt
Prior art date
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EP05809668A
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German (de)
English (en)
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EP1829876A4 (fr
Inventor
Rintaro Yamada
Minoru Seto
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Asahi Kasei Pharma Corp
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Asahi Kasei Pharma Corp
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Publication of EP1829876A1 publication Critical patent/EP1829876A1/fr
Publication of EP1829876A4 publication Critical patent/EP1829876A4/fr
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Definitions

  • the present invention relates to a novel nitrogen-containing tricyclic compound or a salt thereof, and a medicament comprising said nitrogen-containing tricyclic compound or a salt thereof as an active ingredient.
  • Movements of cells include contraction, migration, release, aggregation and the like, and phosphorylation of the myosin regulatory light chain is important for these cell movements.
  • the myosin regulatory light chain is a subunit having a molecular weight of 20 kDa and constituting myosin, which exists in smooth muscle cells and various non-muscle cells such as neutrophils, leukocytes, platelets and nerve cells of warm-blooded animals ( Barany, K., et al., Biochemistry of Smooth Muscle Contraction, pp.21-35, 1996 ).
  • Myosin existing in smooth muscle cells and various non-muscle cells such as neutrophils, leukocytes, platelets and nerve cells of warm-blooded animals is constituted by a myosin heavy chain subunit having a molecular weight of about 200 kDa, the myosin regulatory light chain subunit having a molecular weight of about 20 kDa, and a myosin constitutive light chain subunit having a molecular weight of about 17 kDa.
  • the myosin regulatory light chain is mainly phosphorylated by the myosin light chain kinase to increase the activity of myosin ATPase existing in the myosin heavy chain subunit ( Barany, M., et al., Biochemistry of Smooth Muscle Contraction, pp.321-339, 1996 ).
  • the activated myosin having the increased ATPase activity becomes possible to interact with actin and activates movement apparatuses of cytoskeleton to activate cell movements. That is, it is known that activation of myosin relates to cell contraction ( Kamm, K., et al., Annu. Rev. Physiol., 51, pp.299-313, 1989 ). It is also known that activation of myosin relates to change of cell morphology ( Schmidt, J.T. et al., J, Neurobiol., 52 (3), pp.175-188, 2002 ).
  • activation of myosin relates to cell migration ( Niggli, V., FEBS Lett., 445, pp.69-72, 1999 ). Further, it is known that activation of myosin relates to cell release ( Kitani, S., et al., Biochem. Biophys. Res. Commun., 183, pp.48-54, 1992 ). It is further known that activation of myosin relates to cell aggregation ( Itoh, K., et al., Biochim. Biophys. Acta., 1136, pp.52-56, 1992 ). It is also known that activation of myosin relates to cell apoptosis ( Mills, J.C.
  • an agent which inhibits the phosphorylation of the myosin regulatory light chain suppresses cell contraction, regulates change of cell morphology, suppresses cell migration, suppresses cell release, suppresses cell aggregation and suppresses cell apoptosis.
  • Cell contraction is deeply involved in diseases relating to contraction of various smooth muscle layers.
  • diseases include, for example, hypertension (Samlyo, A.P., et al., Rev. Physiol. Biochem. Pharmacol., Vol. 134, pp.209-234, 1999 ), angina pectoris ( Shimokawa et al., Cardiovasc. Res., Vol. 43, No. 4, pp.1029-1039, 1999 ; Satoh, H., et al., Jpn. J. Pharmacol., 79 (suppl.), p.211, 1999 ), cerebral vascular spasm ( M.
  • Change of cell morphology is deeply involved in diseases relating to morphological change of various cells.
  • the diseases relating to change of cell morphology include, for example, various nerve dysfunctions as those relating to nerve cells.
  • nerve dysfunctions for example, neural damages caused by trauma, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, diabetic retinopathy, glaucoma and the like can be exemplified ( Arakawa, Y., et al., BIO Clinica, 17 (13), pp.26-28, 2002 ).
  • cell migration is deeply involved in diseases relating to migration of various cells. Examples of such diseases include, for example, cancer invasion and metastasis ( Itoh, K. et al., Nat. Med., Vol.
  • cell release is deeply involved in various allergies and the like ( Keane-Myers A. et al., Curr. Allergy Asthma Rep., 1(6):550-557, 2001 ), and further, cell aggregation is considered to be deeply involved in thrombosis and the like ( Nakai, K. et al., Blood, Vol. 90, No. 10, pp.3736-42., 1997 ). Further, it is known that cell apoptosis is involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and glaucoma, viral diseases, hepatic diseases and the like ( Thompson, C.B., Science, Vol. 267, pp.1456-1462, 1995 ).
  • the inhibitor of the phosphorylation of myosin regulatory light chain of the present invention which is an agent inhibiting the phosphorylation of the myosin regulatory light chain, is useful as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis.
  • isoquinoline derivatives As agents that inhibit phosphorylation of the myosin regulatory light chain, isoquinoline derivatives are known. It has been reported that 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) inhibits phosphorylation of the myosin regulatory light chain of mesenteric artery ( Suzuki, A. et al., Br. J. Pharmacol., 109, pp.703-712, 1993 ), iris smooth muscle ( Howe, P.H. et al., Biochem J., 255, pp.423-429, 1988 ), and astrocyte ( Mobley P.L., et al., Exp. Cell Res., 214, pp.55-66, 1994 ). 5-Substituted isoquinoline derivatives that inhibit phosphorylation of the myosin regulatory light chain are also known (International Patent Publication No. 2004/009555 ). However, all of these compounds are bicyclic compounds.
  • An object of the present invention is to provide a novel compound having an action of strongly inhibiting phosphorylation of the myosin regulatory light chain.
  • the inventors of the present invention synthesized various novel compounds and studied pharmacological actions thereof.
  • the compounds represented by the following formula (1) and salts thereof had the desired pharmacological action, and were useful as an active ingredient of a medicament for prophylactic and/or therapeutic treatment of diseases relating to cell contraction, those relating to change of cell morphology, those relating to cell migration, those relating to cell release, those relating to cell aggregation, and those relating to cell apoptosis.
  • the compounds of the present invention are compounds having a tricyclic structure, and have a structure different from that of the isoquinoline derivatives disclosed in the above-mentioned publications (International Patent Publication No.
  • the present invention thus provides the compounds and salts thereof described below.
  • the present invention provides a medicament containing a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient.
  • the aforementioned medicament has an inhibitory action on phosphorylation of myosin regulatory light chain, and is useful as a medicament for prophylactic and/or therapeutic treatment of, for example, a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis and the like.
  • a medicament for decreasing phosphorylation amount of myosin regulatory light chain in a cell which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell contraction inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having an action to regulate change of cell morphology, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell migration inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell release inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell aggregation inhibitory action, which comprises a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof as an active ingredient, a medicament having a cell having aggregat
  • the present invention also provides an inhibitor of the phosphorylation of myosin regulatory light chain containing a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof, and an inhibitor of the Rho/Rho kinase pathway comprising a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof.
  • the present invention further provides a medicament comprising a combination of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof and a jointly-used drug.
  • the aforementioned combined medicament is useful as a medicament for prophylactic and/or therapeutic treatment of, for example, a disease relating to cell contraction, a disease relating to change of cell morphology, a disease relating to cell migration, a disease relating to cell release, a disease relating to cell aggregation, and/or a disease relating to cell apoptosis and the like.
  • the present invention also provides a medicament for use in prophylactic and/or therapeutic treatment of a disease relating to cell contraction, which comprises a combination of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof and a jointly-used drug, a medicament for use in prophylactic and/or therapeutic treatment of a disease relating to change of cell morphology, which comprises a combination of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof and a jointly-used drug, a medicament for use in prophylactic and/or therapeutic treatment of a disease relating to cell migration, which comprises a combination of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof and a jointly-used drug, a medicament for use in prophylactic and/or therapeutic treatment of a disease relating to cell release, which comprises a combination of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof and a jointly-used drug, a medicament for use in prophylactic and/or therapeutic treatment of a
  • the present invention provides use of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof for manufacture of the aforementioned medicaments.
  • the present invention also provides a method for prophylactic and/or therapeutic treatment of a disease relating to cell contraction, disease relating to change of cell morphology, disease relating to cell migration, disease relating to cell release, disease relating to cell aggregation, and/or disease relating to cell apoptosis and the like, which comprises the step of administrating a prophylactically and/or therapeutically effective amount of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof to a mammal including human, a method for decreasing phosphorylation amount of myosin regulatory light chain in a cell, which comprises the step of administrating an effective amount of a compound represented by the aforementioned formula (1) or a physiologically acceptable salt thereof to a mammal including human, a method for inhibiting cell contraction, which comprises the step of administrating an effective amount of a compound represented by
  • the compounds of the present invention represented by the formula (1) have inhibitory activity against the myosin regulatory light chain phosphorylation, and are useful as active ingredients of medicaments for prophylactic and/or therapeutic treatment of, for example, diseases relating to contraction of various cells, diseases relating to morphological change of various cells, diseases relating to migration of various cells, diseases relating to release of various cells, diseases relating to aggregation of various cells, diseases relating to apoptosis of various cells, diseases relating to abnormal gene expression in various cells and the like.
  • the alkyl group mentioned in this specification may be a linear or branched alkyl group, and for example, a lower alkyl group is preferred.
  • the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms, and specific examples are, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, secondary butyl group, tertiary butyl group, pentyl group, 2-methylbutyl group, hexyl group and the like.
  • cycloalkyl is a saturated alicyclic hydrocarbon group, and examples include, for example, a monocyclic C 3-9 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl, bicyclic or tricyclic C 6-10 cycloalkyl such as adamantly and the like.
  • lower cycloalkyl include, for example, a C 3-6 cycloalkyl and the like.
  • aryl include a monocyclic or condensed polycyclic aromatic hydrocarbon group.
  • a C 6-14 aryl group such as phenyl, naphthyl, anthryl, phenanthryl, and acenaphthylenyl, are preferred, phenyl, 1-naphthyl, 2-naphthyl and the like are especially preferred, and phenyl is particularly preferred.
  • heterocyclic group examples include, for example, an aromatic heterocyclic group and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) containing 1 to 3 kinds (preferably 1 to 2 kinds) of at least one (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as atoms constituting the ring system (ring atoms).
  • aromatic heterocyclic group containing 1 to 3 kinds (preferably 1 to 2 kinds) of at least one (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like as atoms constituting the ring system (ring atoms).
  • aromatic heterocyclic group examples include, for example, a 5-or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • a 5-or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazo
  • Examples also include a 8- to 12-membered condensed aromatic heterocyclic group (preferably a heterocyclic group comprising a 5-or 6-membered aromatic monocyclic heterocyclic group among those mentioned above condensing to benzene ring, or a heterocyclic group comprising two of the same or different 5- or 6-membered aromatic monocyclic heterocyclic groups among those mentioned above, more preferably a heterocyclic group comprising a 5- or 6-membered aromatic monocyclic heterocyclic group among those mentioned above condensing to benzene ring), such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquino
  • non-aromatic heterocyclic group examples include, for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group), such as oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, 2(1H)-oxotetrahydropyrimidyl, and homopiperazinyl, a non-aromatic heterocyclic group corresponding to the aforementioned aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group a part or all of which double bonds are saturated, such as 1,2,3,4-
  • R 1 , R 5 , R 6 , R 7 , and R 8 independently include hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, amino group, an alkylamino group, and an aryl amino group.
  • halogen atom examples include fluorine atom, chlorine atom, bromine atom, and iodine atom, and fluorine atom, chlorine atom, or bromine atom are preferred.
  • R 1 examples include hydrogen atom, chlorine atom, and hydroxyl group.
  • Preferred examples of R 1 include hydrogen atom, and hydroxyl group. It is also preferred that these two groups are chosen as R 1 , and it is also preferred that either hydrogen atom or hydroxyl group is selected.
  • R 1 include fluorine atom, bromine atom, iodine atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, amino group, an alkylamino group, and an arylamino group. It is preferred that all of R 5 , R 6 , R 7 , and R 8 are hydrogen atoms.
  • R 5 , R 6 , R 7 , and R 8 are hydrogen atoms.
  • examples of the "alkyl group" include the aforementioned lower alkyl group and the like, and preferred examples include methyl, and ethyl. It is preferred that one of R 1 , R 5 , R 6 , R 7 , or R 8 is an alkyl group, and the others are hydrogen atoms. It is also preferred that, for example, R 1 is hydroxyl group, one of R 5 , R 6 , R 7 , or R 8 is an alkyl group, and the others are hydrogen atoms.
  • examples of the "alkenyl group” include a C 2-6 alkenyl group, such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl, and preferred examples include vinyl and allyl.
  • alkenyl group include a C 2-6 alkenyl group, such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-buteny
  • R 1 , R 5 , R 6 , R 7 , and R 8 is an alkenyl group, and the others are hydrogen atoms. It is also preferred that, for example, R 1 is hydroxyl group, one of R 5 , R 6 , R 7 , and R 8 is an alkenyl group, and the others are hydrogen atoms.
  • examples of the "alkynyl group” include, for example, a C 2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl, and preferred examples include ethynyl and 1-propynyl.
  • a C 2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,
  • R 1 , R 5 , R 6 , R 7 , and R 8 is an alkynyl group, and the others are hydrogen atoms. It is also preferred that, for example, R 1 is hydroxyl group, one of R 5 , R 6 , R 7 , and R 8 is an alkynyl group, and the others are hydrogen atoms.
  • examples of the "alkoxyl group” include, for example, a C 1-4 alkoxyl group such as methoxy, ethoxy, 1-propoxy, isopropoxy, 1-butoxy, isobutoxy, and t-butoxy and the like, and preferred example include methoxy and ethoxy. It is preferred that, for example, one of R 1 , R 5 , R 6 , R 7 , or R 8 is an alkoxyl group, and the others are hydrogen atoms. It is also preferred that, for example, R 1 is hydroxyl group, one of R 5 , R 6 , R 7 , or R 8 is an alkoxyl group, and the others are hydrogen atoms.
  • examples of the "alkylamino group” include a mono(lower alkyl)amino group, and a di(lower alkyl)amino groups.
  • examples of the mono(lower alkyl)amino group include, for example, a mono(C 1-6 )alkylamino group such as methylamino, ethylamino, and propylamino
  • examples of the di(lower alkyl)amino group include a di(C 1-6 )alkylamino groups such as dimethylamino, and diethylamino.
  • R 1 , R 5 , R 6 , R 7 , or R 8 is an alkylamino group, and the others are hydrogen atoms. It is also preferred that, for example, R 1 is hydroxyl group, one of R 5 , R 6 , R 7 , and R 8 is an alkylamino group, and the others are hydrogen atoms.
  • the "aryl amino group" is an amino group substituted with an aryl group, and examples include, for example, a monoarylamino group, and a diarylamino groups.
  • aryl group in the aryl amino group examples include the aforementioned groups, and preferred examples include phenylamino. It is preferred that, for example, one of R 1 , R 5 , R 6 , R 7 , or R 8 is an arylamino group, and the others are hydrogen atoms. It is also preferred that, for example, R 1 is hydroxyl group, one of R 5 , R 6 , R 7 , or R 8 is an aryl amino group, and the others are hydrogen atoms.
  • R 2 , R 3 , and R 4 may be the same or different, and they are preferably represent hydrogen atom, or a lower alkyl group, more preferably hydrogen atom, or methyl group.
  • substituents are hydrogen atoms, and it is also preferred that an arbitrary one of these substituents is methyl group, and all of the remaining substituents are hydrogen atoms.
  • Preferred example of -CH(R 2 )-CH(R 3 )- include -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, and -CH 2 -CH(CH 3 )-, and most preferred examples include -CH 2 -CH 2 - (ethylene group).
  • a 1 , A 11 , A 2 , and A 21 may be the same or different, and they preferably represent hydrogen atom, or a lower alkyl group, more preferably hydrogen atom, or methyl group. It is particularly preferred that all of these substituents are hydrogen atoms, and it is also preferred that an arbitrary one of these substituents is methyl group, and all of the remaining substituents are hydrogen atoms.
  • Y represents -CH(A 3 )-, -CH(A 3 )-C(A4)(A4i)-, -CH(A 3 )-C(A 4 )(A 41 )-C(A 5 ) A 51 )-, or a single bond, and as for -CH(A 3 )-C(A 4 )(A 41 )-, and -CH(A 3 )-C(A 4 )(A 41 )-C(A 5 )(A 51 )-, -CH(A 3 )- binds to N (nitrogen atom) bonding to X 2 .
  • a 3 preferably represents hydrogen atom, or a lower alkyl group, and a more preferred example is hydrogen atom.
  • a 3 is also preferably a lower alkyl group, and particularly preferred examples are methyl group, and ethyl group.
  • a 4 and A 41 independently represent hydrogen atom, or a lower alkyl group, and it is preferred that, for example, both of them represent hydrogen atom. It is also preferred that either one of A 4 and A 41 is hydrogen atom, and the other is a lower alkyl group. Further, it is also preferred that A 4 4 and A 41 are lower alkyl groups, which may be the same or different. Preferred examples of the lower alkyl group as A 4 or A 41 are methyl group, and ethyl group. It is preferred that A 5 and A 51 independently represent hydrogen atom, or a lower alkyl group, and it is preferred that, for example, both of them are hydrogen atoms.
  • a 5 and A 51 are hydrogen atom, and the other is a lower alkyl group. Further, it is also preferred that A 5 and A 51 are lower alkyl groups, which may be the same or different. Preferred examples of the lower alkyl group as A 5 or A 51 are methyl group, and ethyl group.
  • Z represents hydroxyl group, or N(A 6 )(A 61 ).
  • Z is preferably hydroxyl group. It is also preferred that Z is N(A 6 )(A 61 ).
  • a 6 is hydrogen atom or an alkyl group, preferably hydrogen atom, or a lower alkyl group, most preferably hydrogen atom, or methyl group. It is also preferred that, for example, A 6 represents either one of them, or a combination of two of them.
  • a 61 represents hydrogen atom, an alkyl group, an alkyl group substituted with an aryl group, an alkyl group substituted with an aromatic heterocyclic group, an alkyl group substituted with carboxyl group, an alkyl group substituted with cyano group, an alkyl group substituted with hydroxyl group, an alkyl group substituted with an alkoxy group, an alkyl group substituted with a substituted alkoxy group, an alkyl group substituted with amino group, an alkyl group substituted with an alkylamino group, an alkyl group substituted with aminocarbonyl group, an alkyl group substituted with an alkylaminocarbonyloxy group, an alkyl group substituted with a cycloalkylaminocarbonyloxy group, an alkyl group substituted with an arylaminocarbonyloxy group, an alkyl group substituted with mercapto group, an alkyl group substituted with an alkylthio group, an alkyl group substitute
  • Examples of A 61 include, for example, hydrogen atom, a lower alkyl group, a lower alkyl group substituted with an aryl group, a lower alkyl group substituted with carboxyl group, a lower alkyl group substituted with cyano group, a lower alkyl group substituted with hydroxyl group, a lower alkyl group substituted with a lower alkoxy group, a lower alkyl group substituted with amino group, a lower alkyl group substituted with a lower alkylamino group, a lower alkyl group substituted with aminocarbonyl group, a lower alkyl group substituted with alkylaminocarbonyloxy group, a lower alkyl group substituted with a cycloalkylaminocarbonyloxy group, a lower alkyl group substituted with an arylaminocarbonyloxy group, a lower alkyl group substituted with mercapto group, a lower alkyl group substituted with a lower alkylthio group
  • a 61 is preferably hydrogen atom. Further, A 61 is also preferably a lower alkyl group, and this lower alkyl group is most preferably methyl group, or ethyl group. It is also preferred that, for example, A 61 represents either one of them, or a combination of two of them. A 61 is also preferably an a lower alkyl group substituted with an aryl group.
  • Examples of the lower alkyl group substituted with an aryl group herein referred to include a C 7-10 aralkyl group and the like, and examples include benzyl group, and 2-phenylethyl group. Particularly preferred examples include benzyl group.
  • These groups may be substituted with a lower alkyl group, a halogen atom, a lower alkyl group substituted with a halogen atom, an alkyl group substituted with carboxyl group, an aryl group, a heterocyclic group, hydroxyl group, an alkoxy group which may be halogenated, an alkylenedioxy group, an alkyl group substituted with an alkoxycarbonyl group, nitro group, amino group, an alkylamino group, an alkyl group substituted with hydroxyl group, an alkylamino group substituted with hydroxyl group, an alkylamino group substituted with an alkyl group substituted with hydroxyl group, an alkylamino group substituted with an alkyl group substituted with hydroxyl group, an alkylcarbonylamino group, an alkylamino group substituted with an alkylcarbonyl group, an alkylsulfonylamino group, an arylsulfonyla
  • One to four, preferably one or two, of these groups may substitute on the aryl ring (provided that only one alkylenedioxy group can substitute on the aryl ring), and when two or more substituents substitute, the substituents are independent from each other, or one another, and may be the same or different.
  • the substitution positions of these substituents may be, for example, 2-, 3-, 4-, 5-, or 6-position.
  • the substitution position is, for example, 2-, 3-, or 4-position, 3-position, or 4-position is preferred, and the 4-position is most preferred.
  • substitution positions are preferably (2-position, 3-position), (2-position, 4-position), (2-position, 5-position), (3-position, 4-position), or (3-position, 5-position), particularly preferably (3-position, 4-position), or (3-position, 5-position).
  • Preferred examples of the substituent of the "lower alkyl group substituted with an aryl group” include a lower alkyl group, and particularly preferred examples include methyl group, and ethyl group.
  • Preferred examples of the substituent of the "lower alkyl group substituted with an aryl group” also include a halogen atom, and particularly preferred examples include fluorine atom, chlorine atom, and bromine atom.
  • Preferred examples of the substituent of the lower alkyl group substituted with an aryl group also include a lower alkyl group substituted with a halogen atom
  • examples of the "lower alkyl group substituted with a halogen atom" include, for example, a lower alkyl group having 1 to 5 halogen atoms (for example, fluorine atom, chlorine atom, bromine atom, or iodine atom and the like), and specific examples include, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl and the like.
  • Examples of the substituent of the "lower alkyl group substituted with an aryl group” include an alkyl group substituted with carboxyl group, and particularly preferred examples of the substituent of the "alkyl group substituted with carboxyl group” include a lower alkyl group substituted with one or two (preferably one) carboxyl groups, and specific examples include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl and the like. Preferred examples of the substituent of the "lower alkyl group substituted with an aryl group” also include an aryl group.
  • the "aryl” is the same as that described above.
  • Examples of the substituent of the "lower alkyl group substituted with an aryl group” also include a heterocyclic group.
  • heterocyclic group examples include an aromatic heterocyclic group, a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) and the like, as described above.
  • aromatic heterocyclic group for example, a 5- or 6- membered heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, and triazolyl is preferred
  • saturated or unsaturated non-aromatic heterocyclic group a 5- or 6- membered heterocyclic group such as pyrrolidinyl, morpholinyl, piperidinyl, and piperazinyl is preferred.
  • substituent of the "lower alkyl group substituted with an aryl group hydroxyl group is also preferred.
  • an alkoxy group which may be halogenated is also preferred, and particularly preferred examples include a lower alkoxy group (for example, a C 1-6 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy) which may have 1 to 5 halogen atoms (for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like), and examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like.
  • a lower alkoxy group for example, a C 1-6 alkoxy group such as methoxy, ethoxy, propoxy, iso
  • an alkylenedioxy group is also preferred, and examples include, for example, methylenedioxy, ethylenedioxy and the like.
  • an alkyl group substituted with an alkoxycarbonyl group is also preferred, and the number of the alkoxycarbonyl as the substituent is preferably 1 or 2.
  • a lower alkyl group substituted with a lower alkoxycarbonyl group is particularly preferred, and specific examples include methoxycarbonylmethyl, 2-(methoxycarbonyl)ethyl, 3-(methoxycarbonyl)propyl, ethoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl, and 3-(ethoxycarbonyl)propyl.
  • substituent of the "lower alkyl group substituted with an aryl group nitro group is also preferred.
  • amino group is also preferred.
  • an alkylamino group is also preferred, and examples of the “alkylamino group” include, for example, a mono(lower alkyl)amino group, and a di(lower alkyl)amino group.
  • Examples of the mono(lower alkyl)amino group include, for example, a mono(C 1-6 alkyl)amino group such as methylamino, ethylamino, and propylamino and the like, and examples of the di(lower alkyl)amino group include, for example, a di(C 1-6 alkyl)amino group such as dimethylamino, and diethylamino and the like.
  • the substituent of the "lower alkyl group substituted with an aryl group” an alkyl group substituted with hydroxyl group is also preferred, and a lower alkyl group substituted with hydroxyl group is particularly preferred.
  • alkylamino group substituted with hydroxyl group means an amino group substituted with one or two alkyl groups substituted with hydroxyl group.
  • An amino group substituted with one or two lower alkyl groups substituted with hydroxyl group is particularly preferred, and specific examples include 2-(2-hydroxyethyl)amino, 3-(3-hydroxypropyl)amino, 2-(3-hydroxypropyl)amino, 4-(4-hydroxybutyl)amino, di(2-hydroxyethyl)amino, bis(3-hydroxypropyl)amino and the like.
  • substituent of the "lower alkyl group substituted with an aryl group” a (hydroxy-substituted alkyl)(alkyl)amino group is also preferred.
  • (hydroxy-substituted alkyl)(alkyl)amino group means amino group substituted with one alkyl group substituted with hydroxyl group and one alkyl group, and an amino group substituted with one lower alkyl group substituted with hydroxyl group and one lower alkyl group is particularly preferred.
  • Specific examples include (2-hydroxyethyl)(methyl)amino, (3-hydroxypropyl)(methyl)amino, (2-hydroxypropyl)(methyl)amino, (4-hydroxybutyl)(methyl)amino, (2-hydroxyethyl)(ethyl)amino, (3-hydroxypropyl)(ethyl)amino, (2-hydroxypropyl)(ethyl)amino, (4-hydroxybutyl)(ethyl)amino and the like.
  • an alkylcarbonylamino group is also preferred, and a lower alkylcarbonylamino group is particularly referred. Specific examples include a C 1-6 alkylcarbonylamino group such as acetylamino, propionylamino, and butyrylamino.
  • an alkylamino group substituted with an alkylcarbonyl group is also preferred.
  • alkylamino group substituted with an alkylcarbonyl group means an amino group substituted with one alkylcarbonyl group and an alkyl group, and an amino group substituted with one lower alkylcarbonyl group and one lower alkyl group is particularly preferred.
  • Specific examples include a C 2-8 alkylcarbonylamino group such as acetyl(methyl)amino, propionyl(methyl)amino, butyryl(methyl)amino, acetyl(ethyl)amino, propionyl(ethyl)amino, and butyryl(ethyl)amino.
  • an alkylsulfonylamino group is also preferred, and a lower alkylsulfonylamino group is particularly preferred. Specific examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino and the like.
  • an arylsulfonylamino group is also preferred.
  • aryl in the "arylsulfonylamino" is the same as that described above, and as specific examples of the arylsulfonylamino, phenylsulfonylamino, 1-naphthylsulfonylamino, 2-naphthylsulfonylamino and the like are preferred, and phenylsulfonylamino is particularly preferred.
  • an alkyl group substituted with an aromatic heterocyclic group is also preferred.
  • a lower alkyl group substituted with an aromatic heterocyclic group is preferred.
  • the aromatic heterocyclic group referred to herein is the same as that described above, and specific examples of the "alkyl group substituted with an aromatic heterocyclic group” include 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl and the like.
  • a lower alkyl group substituted with carboxyl group is also preferred.
  • the lower alkyl group may be substituted with one or more carboxyl groups, and a lower alkyl group substituted with one of carboxyl group is generally preferred.
  • Preferred examples include carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and 4-carboxybutyl. In particular, carboxymethyl and 2-carboxyethyl are preferred.
  • Preferred examples also include either one of or a combination of any two of the aforementioned groups.
  • a lower alkyl group substituted with cyano group is also preferred.
  • the lower alkyl group may be substituted with one or more cyano groups.
  • a lower alkyl group substituted with one of cyano group is generally preferred, and preferred examples include cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, and 4-cyanobutyl.
  • a lower alkyl group substituted with hydroxyl group is also preferred.
  • the lower alkyl group may be substituted with one or more hydroxyl groups.
  • a lower alkyl group substituted with one of hydroxyl group is generally preferred, and preferred examples include 2-hydroxyethyl, 3-hydroxypropyl, and 4-hydroxybutyl.
  • 2-hydroxyethyl, and 3-hydroxypropyl are preferred. Preferred examples also include either one of or a combination of any two of these groups.
  • a lower alkyl group substituted with two of hydroxyl groups is also preferred, and examples include 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2-(1,3-dihydroxy)propyl, 2-(3,4-dihydroxy)butyl, 2,3-dihydroxybutyl, 2-(1,5-dihydroxy)pentyl, 3-(1,5-dihydroxy)pentyl and the like.
  • a lower alkyl group substituted with a lower alkoxyl group is also preferred.
  • the lower alkoxyl group include linear or branched alkoxyl groups having 1 to 4 carbon atoms, and specific examples include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group and the like. Methoxy group and ethoxy group are preferred.
  • the lower alkyl group may be substituted with one or more lower alkoxyl groups.
  • a lower alkyl group substituted with one of lower alkoxyl group is generally preferred, and preferred examples include 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, and 4-methoxybutyl. In particular, 2-methoxyethyl and 3-methoxypropyl are preferred.
  • Preferred examples also include either one of or a combination of any two of these groups.
  • a lower alkyl group substituted with a substituted alkoxy group is also preferred.
  • substituted an alkoxy group herein referred to include an alkoxy group substituted with hydroxyl group, an alkoxy group, amino group, an alkylamino group, an acylamino group, mercapto group, alkylthio group, or an acylthio group.
  • One or two of these groups may independently substitute on the alkoxy group, and an alkoxy group substituted with one of these groups is generally preferred.
  • Preferred examples of the "lower alkyl group substituted with a substituted alkoxy group” include a lower alkyl group substituted with an alkoxy group substituted with hydroxyl group, and specific examples include 2-(2-hydroxyethoxy)ethyl, 2-(3-hydroxypropoxy)ethyl, 3-(2-hydroxyethoxy)propyl, 3-(3-hydroxypropoxy)propyl and the like.
  • Preferred examples of the "lower alkyl group substituted with a substituted alkoxy group” further include a lower alkyl group substituted with an alkoxy group substituted with an alkoxy group, and preferred examples of both alkoxy groups include a lower alkyloxy.
  • lower alkyl group substituted with an alkoxy group substituted with an alkoxy group include 2-(2-methoxyethoxy)ethyl, 2-(3-methoxypropoxy)ethyl, 3-(2-methoxyethoxy)propyl, 3-(3-methoxypropoxy)propyl, 2-(2-ethoxyethoxy)ethyl, 2-(3-ethoxypropoxy)ethyl, 3-(2-ethoxyethoxy)propyl, 3-(3-ethoxypropoxy)propyl and the like.
  • lower alkyl group substituted with a substituted alkoxy group include a lower alkyl group substituted with an alkoxy group substituted with amino group, and specific examples include 2-(2-aminoethoxy)ethyl, 2-(3-aminopropoxy)ethyl, 3-(2-aminoethoxy)propyl, 3-(3-aminopropoxy)propyl and the like.
  • Preferred examples of the "lower alkyl group substituted with a substituted alkoxy group” further include a lower alkyl group substituted with an alkoxy group substituted with an alkylamino group
  • examples of the "alkylamino group” in this group include, for example, a mono(lower alkyl)amino group, and a di(lower alkyl)amino group.
  • examples of the mono(lower alkyl)amino group include, for example, a mono(C 1-6 alkyl)amino group such as methylamino, ethylamino, and propylamino and the like.
  • di(lower alkyl)amino group examples include, for example, a di(C 1-6 alkyl)amino group such as dimethylamino, and diethylamino and the like.
  • specific examples of the lower alkyl group substituted with an alkoxy group substituted with an alkylamino group include a lower alkyl group substituted with an alkoxy group substituted with a mono(lower alkyl)amino group such as 2-(2-(methylamino)ethoxy)ethyl, 2-(3-(methylamino)propoxy)ethyl, 3-(2-(methylamino)ethoxy)propyl, 3-(3-(methylamino)propoxy)propyl, 2-(2-(ethylamino)ethoxy)ethyl, 2-(3-(ethylamino)propoxy)ethyl, 3-(2-(ethylamino)ethoxy)propyl, and 3-(3-(eth)
  • lower alkyl group substituted with a substituted alkoxy group examples include a lower alkyl group substituted with an alkoxy group substituted with an acylamino group
  • acylamino group examples include, for example, an alkylcarbonylamino group, and an arylcarbonylamino group ("alkyl” and “aryl” herein referred to are the same as those described above), and particularly preferred examples include an alkylcarbonylamino group.
  • lower alkyl group substituted with an alkoxy group substituted with an acylamino group examples include 2-(2-(acetylamino)ethoxy)ethyl, 2-(3-(acetylamino)propoxy)ethyl, 3-(2-(acetylamino)ethoxy)propyl, 3-(3-(acetylamino)propoxy)propyl, 2-(2-(propionylamino)ethoxy)ethyl, 2-(3-(propionylamino)propoxy)ethyl, 3-(2-(propionylamino)ethoxy)propyl, 3-(3-(propionylamino)propoxy)propyl and the like.
  • Preferred examples of the "lower alkyl group substituted with a substituted alkoxy group” further include a lower alkyl group substituted with an alkoxy group substituted with mercapto group, and specific examples include 2-(2-mercaptoethoxy)ethyl, 2-(3-mercaptopropoxy)ethyl, 3-(2-mercaptoethoxy)propyl, 3-(3-mercaptopropoxy)propyl and the like.
  • Preferred examples the "lower alkyl group substituted with a substituted alkoxy group” further include a lower alkyl group substituted with an alkoxy group substituted with an alkylthio group, and preferred examples of the alkylthio group in this group include a lower alkylthio.
  • lower alkyl group substituted with an alkoxy group substituted with an alkylthio group examples include 2-(2-(methylthio)ethoxy)ethyl, 2-(3-(methylthio)propoxy)ethyl, 3-(2-(methylthio)ethoxy)propyl, 3-(3-(methylthio)propoxy)propyl, 2-(2-(ethylthio)ethoxy)ethyl, 2-(3-(ethylthio)propoxy)ethyl, 3-(2-(ethylthio)ethoxy)propyl, 3-(3-(ethylthio)propoxy)propyl and the like.
  • lower alkyl group substituted with a substituted alkoxy group examples include a lower alkyl group substituted with an alkoxy group substituted with an acylthio group.
  • acylthio group examples include, for example, an alkylcarbonylthio group, and an arylcarbonylthio group ("alkyl” and “aryl” herein referred to are the same as those described above), and particularly preferred examples include an alkylcarbonylthio group.
  • lower alkyl group substituted with an alkoxy group substituted with an acylthio group examples include 2-(2-(acetylthio)ethoxy)ethyl, 2-(3-(acetylthio)propoxy)ethyl, 3-(2-(acetylthio)ethoxy)propyl, 3-(3-(acetylthio)propoxy)propyl, 2-(2-(propionylthio)ethoxy)ethyl, 2-(3-(propionylthio)propoxy)ethyl, 3-(2-(propionylthio)ethoxy)propyl, 3-(3-(propionylthio)propoxy)propyl and the like.
  • a lower alkyl group substituted with amino group is also preferred.
  • the lower alkyl group may be substituted with one or more amino groups, and a lower alkyl group substituted with one amino group is generally preferred.
  • Preferred examples include 2-aminoethyl, 3-aminopropyl, 2-aminopropyl, and 4-aminobutyl, and 2-aminoethyl, and 3-aminopropyl are particularly preferred.
  • the "lower alkyl group substituted with amino group” may be further substituted with hydroxyl group.
  • the lower alkyl group is usually substituted with one hydroxyl group. Specific examples include 2-amino-3-hydroxypropyl, 3-amino-2-hydroxypropyl, 3-amino-4-hydroxybutyl and the like.
  • a lower alkyl group substituted with a lower alkylamino group is also preferred.
  • the lower alkylamino group include a monoalkylamino group and dialkylamino group substituted with one or two lower alkyl groups.
  • the dialkylamino group the alkyl groups may be the same or different.
  • the lower alkyl group may be substituted with one or more of the amino groups, and a lower alkyl group substituted with one alkylamino group is generally preferred.
  • Preferred examples include 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 3-(methylamino)propyl, 3-(dimethylamino)propyl, 4-(methylamino)butyl, and 4-(dimethylamino)butyl, and 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 3-(methylamino)propyl, and 3-(dimethylamino)propyl are particularly preferred.
  • the "lower alkyl group substituted with a lower alkylamino group” may be further substituted with hydroxyl group.
  • the lower alkyl group is usually substituted with one hydroxyl group, and specific examples include 2-(methylamino)-3-hydroxypropyl, 3-(methylamino)-2-hydroxypropyl, 3-(methylamino)-4-hydroxybutyl, 2-(dimethylamino)-3-hydroxypropyl, 3-(dimethylamino)-2-hydroxypropyl, 3-(dimethylamino)-4-hydroxybutyl and the like.
  • a lower alkyl group substituted with aminocarbonyl group is also preferred.
  • the lower alkyl group may be substituted with one or more aminocarbonyl groups.
  • a lower alkyl group substituted with one of aminocarbonyl group is generally preferred, and preferred examples include, for example, aminocarbonylmethyl and aminocarbonylethyl. Preferred examples also include either one of or a combination of any two of these groups.
  • an alkyl group substituted with an alkylaminocarbonyloxy group is also preferred.
  • alkyl group substituted with an alkylaminocarbonyloxy group include 2-(methylaminocarbonyloxy)ethyl, 2-(ethylaminocarbonyloxy)ethyl, 2-(propylaminocarbonyloxy)ethyl, 2-(isopropylaminocarbonyloxy)ethyl, 3-(methylaminocarbonyloxy)propyl, 3-(ethylaminocarbonyloxy)propyl, 3-(propylaminocarbonyloxy)propyl, 3-(isopropylaminocarbonyloxy)propyl, 4-(methylaminocarbonyloxy)butyl, 4-(ethylaminocarbonyloxy)butyl, 4-(propylaminocarbonyloxy)butyl, 4-(isopropylaminocarbonyloxy)butyl and the like.
  • an alkyl group substituted with a cycloalkylaminocarbonyloxy group is also preferred.
  • Preferred specific examples of the alkyl group substituted with a cycloalkylaminocarbonyloxy group include 2-(cyclopropylaminocarbonyloxy)ethyl, 2-(cyclobutylaminocarbonyloxy)ethyl, 2-(cyclopentylaminocarbonyloxy)ethyl, 2-(cyclohexylaminocarbonyloxy)ethyl, 3-(cyclopropylaminocarbonyloxy)propyl, 3-(cyclobutylaminocarbonyloxy)propyl, 3-(cyclopentylaminocarbonyloxy)propyl, 3-(cyclohexylaminocarbonyloxy)propyl, 4-(cyclopropylaminocarbonyloxy)butyl, 4-(cyclobutylaminocarbonyloxy)butyl, 4-(cyclopentylaminocarbonyloxy)butyl, 4-(cyclohexylaminocarbonyloxy)butyl and the like
  • an alkyl group substituted with an arylaminocarbonyloxy group is also preferred.
  • an alkyl group substituted with mercapto group is also preferred, and a lower alkyl group substituted with mercapto group is particularly preferred.
  • the lower alkyl group may be substituted with one or more mercapto groups, and an alkyl group substituted with one mercapto group is generally preferred
  • 2-mercaptoethyl, 3-mercaptopropyl, 4-mercaptobutyl, 5-mercaptopentyl and the like are preferred.
  • Preferred examples also include either one of or a combination of any two of the aforementioned groups.
  • an alkyl group substituted with an alkylthio group is also preferred.
  • a lower alkyl group substituted with an alkylthio group is preferred, and a lower alkyl group substituted with a lower alkylthio group is particularly preferred.
  • the lower alkyl group may be substituted with one or more alkylthio groups, and an alkyl group substituted with one alkylthio group is generally preferred.
  • 2-(methylthio)ethyl, 2-(ethylthio)ethyl, 3-(methylthio)propyl, 3-(ethylthio)propyl, 4-(methylthio)butyl, 4-(ethylthio)butyl, 5-(methylthio)pentyl, 5-(ethylthio)pentyl and the like are preferred.
  • Preferred examples also include either one of or a combination of any two of the aforementioned groups.
  • an alkyl group substituted with an acylthio group is also preferred.
  • a lower alkyl group substituted with an acylthio group is preferred, and a lower alkyl group substituted with a C 2-6 alkanoylthio group is particularly preferred.
  • the lower alkyl group may be substituted with one or more acylthio groups, and an alkyl group substituted with one acylthio group is generally preferred.
  • 2-(acetylthio)ethyl, 2-(propionylthio)ethyl, 3-(acetylthio)propyl, 3-(propionylthio)propyl, 4-(acetylthio)butyl, 4-(propionylthio)butyl, 5-(acetylthio)pentyl, 5-(propionylthio)pentyl and the like are preferred.
  • Preferred examples also include either one of or a combination of any two of the aforementioned groups.
  • a 61 a cycloalkyl group is also preferred.
  • the cycloalkyl is the same as that described above, and a lower cycloalkyl group is preferred.
  • a substituted cycloalkyl group is also preferred.
  • a cycloalkyl group substituted with hydroxyl group, an alkoxy group, amino group, an alkylamino group, an acylamino group, mercapto group, alkylthio group, an acylthio group, an alkylsulfonylamino group, or the like is particularly preferred.
  • the cycloalkyl group may be independently substituted with one or two of these groups, and a cycloalkyl, group substituted with one of these group is generally preferred.
  • Preferred examples include a cycloalkyl group substituted with hydroxyl group, and specific examples include 3-hydroxycyclobutyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl and the like. Further, preferred examples include a cycloalkyl group substituted with an alkoxy group, and preferred examples of the alkoxy group in this group include a lower alkyloxy. Specific examples of the cycloalkyl group substituted with an alkoxy group include 3-methoxycyclobutyl, 3-methoxycyclohexyl, 4-methoxycyclohexyl, 3-ethoxycyclobutyl, 3-ethoxycyclohexyl, 4-ethoxycyclohexyl and the like.
  • Preferred examples further include a cycloalkyl group substituted with amino group, and specific examples include 3-aminocyclobutyl, 3-aminocyclohexyl, 4-aminocyclohexyl and the like. Preferred examples further include a cycloalkyl group substituted with an alkylamino group, and examples of the "alkylamino group" in this group include a mono(lower alkyl)amino group, and a di(lower alkyl)amino group.
  • Examples of the mono(lower alkyl)amino group include, for example, a mono(C 1-6 ) alkylamino group such as methylamino, ethylamino, and propylamino and the like, and examples of the di(lower alkyl)amino group include a di(C 1-6 alkyl)amino group such as dimethylamino, and diethylamino and the like.
  • cycloalkyl group substituted with an alkylamino group examples include a cycloalkyl group substituted with a mono(lower alkyl)amino group such as 3-(methylamino)cyclobutyl, 3-(methylamino)cyclohexyl, 4-(methylamino)cyclohexyl, 3-(ethylamino)cyclobutyl, 3-(ethylamino)cyclohexyl, and 4-(ethylamino)cyclohexyl, and a cycloalkyl group substituted with a di(lower alkyl)amino group such as 3-(dimethylamino)cyclobutyl, 3-(dimethylamino)cyclohexyl, 4-(dimethylamino)cyclohexyl, 3-(diethylamino)cyclobutyl, 3-(diethylamino)cyclohexyl, and 4-(diethyla
  • Preferred examples further include a cycloalkyl group substituted with an acylamino group, and examples of the "acylamino group" in this group include an alkylcarbonylamino group, and an arylcarbonylamino group ("alkyl” and “aryl” herein referred to are the same as those described above).
  • An alkylcarbonylamino group is particularly preferred.
  • cycloalkyl group substituted with an acylamino group examples include 3-(acetylamino)cyclobutyl, 3-(acetylamino)cyclohexyl, 4-(acetylamino)cyclohexyl, 3-(propionylamino)cyclobutyl, 3-(propionylamino)cyclohexyl, 4-(propionylamino)cyclohexyl, 3-(butyrylamino)cyclobutyl, 3-(butyrylamino)cyclohexyl, 4-(butyrylamino)cyclohexyl, 3-(isobutyrylamino)cyclobutyl, 3-(isobutyrylamino)cyclohexyl, 4-(isobutyrylamino)cyclohexyl and the like, and particularly preferred examples include 3-(acetylamino)cyclobutyl, 3-(acetylamino)cyclohexyl, 3-(
  • Preferred examples further include a cycloalkyl group substituted with mercapto group, and specific examples include 3-mercaptocyclobutyl, 3-mercaptocyclohexyl, 4-mercaptocyclohexyl and the like. Preferred examples further include a cycloalkyl group substituted with an alkylthio group, and preferred examples of the alkylthio group in this group include a lower alkylthio.
  • cycloalkyl group substituted with an alkylthio group examples include 3-(methylthio)cyclobutyl, 3-(methylthio)cyclohexyl, 4-(methylthio)cyclohexyl, 3-(ethylthio)cyclobutyl, 3-(ethylthio)cyclohexyl, 4-(ethylthio)cyclohexyl and the like.
  • Preferred examples further include a cycloalkyl group substituted with an acylthio group
  • examples of the "acylthio group" in this group include, for example, an alkylcarbonylthio group, and an arylcarbonylthio group ("alkyl” and “aryl” herein referred to are the same as those described above), and an alkylcarbonylthio group is particularly preferred.
  • cycloalkyl group substituted with an acylthio group examples include 3-(acetylthio)cyclobutyl, 3-(acetylthio)cyclohexyl, 4-(acetylthio)cyclohexyl, 3-(propionylthio)cyclobutyl, 3-(propionylthio)cyclohexyl, 4-(propionylthio)cyclohexyl, 3-(butyrylthio)cyclobutyl, 3-(butyrylthio)cyclohexyl, 4-(butyrylthio)cyclohexyl, 3-(isobutyrylthio)cyclobutyl, 3-(isobutyrylthio)cyclohexyl, 4-(isobutyrylthio)cyclohexyl and the like, and particularly preferred examples include 3-(acetylthio)cyclobutyl, 3-(acetylthio)cyclohexyl, and 4-(acetylthi
  • Preferred examples further include a cycloalkyl group substituted with an alkylsulfonylamino group, and examples of the alkylsulfonylamino group in this group include a lower alkylsulfonyl.
  • cycloalkyl group substituted with an alkylsulfonylamino group examples include 3-(methylsulfonylamino)cyclobutyl, 3-(methylsulfonylamino)cyclohexyl, 4-(methylsulfonylamino)cyclohexyl, 3-(ethylsulfonylamino)cyclobutyl, 3-(ethylsulfonylamino)cyclohexyl, 4-(ethylsulfonylamino)cyclohexyl and the like.
  • a 61 examples include carbamimidoyl group.
  • an alkylcarbonyl group is also preferred, a lower alkylcarbonyl group is particularly preferred, and specific examples include acetyl, propionyl, butyryl, and isobutyryl.
  • an arylcarbonyl group is also preferred.
  • the "aryl" in this group is the same as that described above. Examples of the arylcarbonyl group include, for example, phenylcarbonyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.
  • a non-aromatic heterocyclic group is also preferred.
  • the non-aromatic heterocyclic group is the same as that described above.
  • a 4- to 8-membered non-aromatic heterocyclic group is preferred, and particularly preferred examples include a 4- to 6-membered non-aromatic heterocyclic group.
  • the non-aromatic heterocyclic group comprises one or more hetero atoms, and a non-aromatic heterocyclic group comprising one or two hetero atoms is generally preferred.
  • a substituted non-aromatic heterocyclic group comprising one or two nitrogen atoms is also preferred.
  • a 4- to 8-membered non-aromatic heterocyclic group is preferred, and particularly preferred examples include a 4- to 6-membered non-aromatic heterocyclic group.
  • the non-aromatic heterocyclic group is a non-aromatic heterocyclic group comprising one nitrogen atom, it is preferred that the nitrogen atom constituting the ring is substituted.
  • substituents examples include lower alkyl, lower alkylcarbonyl, arylcarbonyl, lower alkylsulfonyl, arylsulfonyl and the like.
  • Methyl, ethyl, propyl, acetyl, benzoyl, methanesulfonyl, benzenesulfonyl and the like are preferred, and particularly preferred examples include methyl, acetyl, and methanesulfonyl.
  • non-aromatic heterocyclic group comprising one nitrogen atom and substituted with these group
  • these group include 3-azetidin-1-yl, 3-pyrrolidin-1-yl, 3-piperidin-1-yl, 4-piperidin-1-yl and the like.
  • the alkylene moiety of the non-aromatic heterocyclic group may be substituted with one or more oxo groups, and it is generally preferred that the alkylene moiety is substituted with one oxo group.
  • Preferred examples include, for example, tetrahydropyrimidin-2(1H)-on-5-yl, 1,3-dimethyl-tetrahydropyrimidin-2(1H)-on-5-yl and the like.
  • an alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 ) is also preferred.
  • a 7 represents hydrogen atom, an alkyl group, an alkyl group substituted with hydroxyl group, an alkyl group substituted with amino group, an alkyl group substituted with an alkylamino group, an alkyl group substituted with aminocarbonyl group, an alkyl group substituted with an acylamino group, or an alkyl group substituted with cyano group
  • a 71 and A 8 independently represent hydrogen atom, an alkyl group, an alkyl group substituted with an aryl group, an alkyl group substituted with a heterocyclic group, an alkyl group substituted
  • a 7 hydrogen atom is preferred.
  • an alkyl group, an alkyl group substituted with hydroxyl group, an alkyl group substituted with amino group, an alkyl group substituted with an alkylamino group, an alkyl group substituted with an alkylcarbonyl group, or an alkyl group substituted with cyano group is also preferred, and more preferred examples of the alkyl group for these alkyl groups include a lower alkyl group.
  • Preferred examples of A 7 include a lower alkyl group, and particularly preferred examples include methyl, and ethyl. Preferred examples of A 7 also include a lower alkyl group substituted with hydroxyl group.
  • the lower alkyl group may be substituted with one or more hydroxyl groups, and a lower alkyl group substituted with one of hydroxyl group is generally preferred.
  • Specific examples include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl and the like, and particularly preferred examples include 2-hydroxyethyl, and 3-hydroxyethyl.
  • Preferred examples of A 7 also include a lower alkyl group substituted with amino group.
  • the lower alkyl group may be substituted with one or more amino groups, and a lower alkyl group substituted with one of amino group is generally preferred. Specific examples include 2-aminoethyl, 3-aminopropyl, 2-aminopropyl, 4-aminobutyl and the like, and particularly preferred examples include 2-aminoethyl, and 3-aminoethyl.
  • a lower alkyl group substituted with a lower alkylamino group is also preferred.
  • the "lower alkylamino group” include a monoalkylamino group and dialkylamino group substituted with one or two lower alkyl groups.
  • the dialkylamino group the alkyl groups may be the same or different.
  • the lower alkyl group may be substituted with one or more of the amino groups, and a lower alkyl group substituted with one alkylamino group is generally preferred.
  • Preferred examples include 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 3-(methylamino)propyl, 3-(dimethylamino)propyl, 4-(methylamino)butyl, and 4-(dimethylamino)butyl, particularly preferred examples include 2-(methylamino)ethyl, and 3-(methylamino)propyl.
  • Preferred examples of A 7 also include a lower alkyl group substituted with aminocarbonyl group. In this group, the lower alkyl group may be substituted with one or more aminocarbonyl groups, and a lower alkyl group substituted with one of aminocarbonyl group is generally preferred.
  • Preferred examples include, for example, aminocarbonylmethyl, 2-aminocarbonylethyl, and 3-aminocarbonylpropyl.
  • a 7 a lower alkyl group substituted with an acylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more acylamino groups, and a lower alkyl group substituted with one acylamino group is generally preferred.
  • the "acylamino group" in this group include, for example, an alkylcarbonylamino group, and an arylcarbonylamino group ("alkyl" and "aryl” herein referred to are the same as those described above), and particularly preferred examples include an alkylcarbonylamino group.
  • lower alkyl group substituted with an acylamino group examples include 2-(acetylamino)ethyl, 3-(acetylamino)propyl, 2-(propionylamino)ethyl, 3-(propionylamino)propyl and the like.
  • Preferred examples of A 7 also include a lower alkyl group substituted with cyano group.
  • the lower alkyl group may be substituted with one or more cyano groups, and a lower alkyl group substituted with one of cyano group is generally preferred.
  • Specific examples include cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 4-cyanobutyl and the like, and particularly preferred examples include cyanomethyl, and 2-cyanoethyl.
  • -X 3 - carbonyl group is preferred.
  • a 61 an alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 ) (wherein -X 3 - represents carbonyl group) is preferred.
  • Preferred examples of A 71 include hydrogen atom.
  • an alkyl group an alkyl group substituted with an aryl group, an alkyl group substituted with a heterocyclic group, an alkyl group substituted with hydroxyl group, an alkyl group substituted with amino group, an alkyl group substituted with an alkylamino group, an alkyl group substituted with an alkoxy group, and an alkyl group substituted with an acylamino group are preferred, and more preferred examples of the alkyl group for these alkyl groups include a lower alkyl group. Further , as A 61 , a lower alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 ) is also preferred.
  • -X 3 -, A 7 and A 71 are the same as those described above.
  • the lower alkyl group may be substituted with one or more of N(A 7 )(-X 3 -A 71 ), and the lower alkyl group substituted with one of N(A 7 )(-X 3 -A 71 ) is generally preferred.
  • Preferred examples of A 71 include a lower alkyl group, and specific examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Particularly preferred examples include methyl, ethyl and the like.
  • the lower alkyl group may be substituted with 1 to 5 halogen atoms (for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like).
  • halogen atoms for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
  • Preferred specific examples include chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and the like, and more preferred examples include trifluoromethyl, and 2,2,2-trifluoroethyl.
  • a 71 also include a lower alkyl group substituted with an aryl group (aryl is the same as that described above), and specific examples include benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. Preferred are benzyl, 2-phenylethyl and the like.
  • the "aryl ring" moiety of these groups may be substituted with a group similar to A 61 mentioned above.
  • Preferred examples of A 71 also include a lower alkyl group substituted with a heterocyclic group (heterocyclic group is the same as that described above), and examples of the heterocyclic group in this group include “an aromatic heterocyclic group", and a "non-aromatic heterocyclic group".
  • heterocyclic group is the same as that described above
  • examples of the heterocyclic group in this group include "an aromatic heterocyclic group", and a "non-aromatic heterocyclic group”.
  • specific examples of the lower alkyl group substituted with an aromatic heterocyclic group include 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl and the like.
  • lower alkyl group substituted with a heterocyclic group specific examples include oxylanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, tetrahydrofurylmethyl, thiolanylmethyl, piperidylmethyl, tetrahydropyranylmethyl, morpholinylmethyl, thiomorpholinylmethyl, piperazinylmethyl and the like.
  • Preferred examples of A 71 also include a lower alkyl group substituted with hydroxyl group.
  • the lower alkyl group may be substituted with one or more hydroxyl groups, and a lower alkyl group substituted with one of hydroxyl group is generally preferred.
  • Specific examples include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl and the like, and particularly preferred examples include 2-hydroxyethyl, and 3-hydroxyethyl.
  • Preferred examples of A 71 include a lower alkyl group substituted with amino group. In this group, the lower alkyl group may be substituted with one or more amino groups, and a lower alkyl group substituted with one of amino group is generally preferred.
  • a lower alkyl group substituted with a lower alkylamino group is also preferred.
  • the dialkylamino group the alkyl groups may be the same or different.
  • the lower alkyl group may be substituted with one or more of the amino groups, and a lower alkyl group substituted with one alkylamino group is generally preferred.
  • Preferred examples include 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 3-(methylamino)propyl, 3-(dimethylamino)propyl, 4-(methylamino)butyl, and 4-(dimethylamino)butyl, and particularly preferred examples include 2-(methylamino)ethyl, and 3-(methylamino)propyl.
  • a lower alkyl group substituted with an alkoxy group is also preferred.
  • the lower alkoxy group include linear or branched alkoxy having 1 to 4 carbon atoms. Specific examples include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group and the like, and methoxy group, and ethoxy group are preferred.
  • the lower alkyl group may be substituted with one or more lower alkoxy groups, and a lower alkyl group substituted with one alkoxy group is generally preferred.
  • Preferred examples include 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, and 4-methoxybutyl, and 2-methoxyethyl, and 3-methoxypropyl are particularly preferred.
  • a lower alkyl group substituted with an acylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more acylamino groups, and a lower alkyl group substituted with one acylamino group is generally preferred.
  • acylamino group examples include an alkylcarbonylamino group, and an arylcarbonylamino group ("alkyl” and “aryl” herein referred to are the same as those described above).
  • alkyl and aryl herein referred to are the same as those described above.
  • a lower alkyl group substituted with an alkylcarbonylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more alkylcarbonylamino groups, and a lower alkyl group substituted with one of alkylcarbonylamino group is generally preferred.
  • Specific examples include acetylaminomethyl, 2-(acetylamino)ethyl, 3-(acetylamino)propyl, 4-(acetylamino)butyl, propionylaminomethyl, 2-(propionylamino)ethyl, 3-(propionylamino)propyl, 4-(propionylamino)butyl and the like.
  • a lower alkyl group substituted with an arylcarbonylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more arylcarbonylamino groups, and a lower alkyl group substituted with one of arylcarbonylamino group is generally preferred. Specific examples include benzoylaminomethyl, 2-(benzoylamino)ethyl, 3-(benzoylamino)propyl, 4-(benzoylamino)butyl and the like.
  • a cycloalkyl group is also preferred. The cycloalkyl is the same as that described above.
  • a lower cycloalkyl group is preferred, and particularly preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • an aryl group is also preferred. The aryl is the same as that described above, and preferred examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • an aromatic heterocyclic group is also preferred. The aromatic heterocyclic group is the same as that described above, and specific examples include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl and the like.
  • a 7 and A 71 together become an alkylene group, or an alkylene group substituted with an alkyl group to form a ring together with N to which A 7 and A 71 bind and -X 3 -.
  • the alkyl group is preferably a lower alkyl group, and examples of the lower alkyl group include, methyl, and ethyl. More preferred examples include methyl.
  • the ring formed by A 7 and A 71 is preferably a 4- to 7-membered ring, and particularly preferred examples include 4-, 5-, and 6-membered rings.
  • Preferred examples of A 8 include hydrogen atom.
  • an alkyl group an alkyl group substituted with an aryl group, an alkyl group substituted with a heterocyclic group, an alkyl group substituted with hydroxyl group, an alkyl group substituted with amino group, an alkyl group substituted with an alkylamino group, an alkyl group substituted with an alkoxy group, and an alkyl group substituted with an acylamino group are also preferred, and more preferred examples of the alkyl group of these alkyl groups include a lower alkyl group.
  • Preferred examples of A 8 include a lower alkyl group. Specific examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like, and particularly preferred examples include methyl, ethyl and the like. Preferred examples of A 8 include a lower alkyl group substituted with an aryl group (aryl is the same as that described above). Specific examples include benzyl, 2-phenylethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like, and preferred examples include benzyl, 2-phenylethyl and the like.
  • the "aryl ring" moiety of these groups may be substituted with a group similar to A 61 mentioned above.
  • Preferred examples of A 8 include a lower alkyl group substituted with a heterocyclic group (heterocyclic group is the same as that described above), and the heterocyclic group in this group include an "aromatic heterocyclic group", and a "non-aromatic heterocyclic group".
  • specific examples of the lower alkyl group substituted with an aromatic heterocyclic group include 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-pyrrolylmethyl, 3-pyrrolylmethyl and the like.
  • lower alkyl group substituted with a heterocyclic group specific examples include oxylanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, tetrahydrofurylmethyl, thiolanylmethyl, piperidylmethyl, tetrahydropyranylmethyl, morpholinylmethyl, thiomorpholinylmethyl, piperazinylmethyl and the like.
  • Preferred examples of A 8 also include a lower alkyl group substituted with hydroxyl group.
  • the lower alkyl group may be substituted with one or more hydroxyl groups, and a lower alkyl group substituted with one of hydroxyl group is generally preferred.
  • Specific examples include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl and the like, and particularly preferred examples include 2-hydroxyethyl, and 3-hydroxyethyl.
  • Preferred examples of A 8 include a lower alkyl group substituted with amino group. In this group, the lower alkyl group may be substituted with one or more amino groups, and a lower alkyl group substituted with one of amino group is generally preferred.
  • a lower alkyl group substituted with a lower alkylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more lower alkylamino groups, and a lower alkyl group substituted with one of lower alkylamino group is generally preferred.
  • the "lower alkylamino group" herein referred to include a monoalkylamino group, and dialkylamino group, which are substituted with one or two lower alkyl groups.
  • the alkyl groups may be the same or different.
  • the lower alkyl group may be substituted with one or more of the amino groups, and a lower alkyl group substituted with one alkylamino group is generally preferred.
  • Preferred examples include 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 3-(methylamino)propyl, 3-(dimethylamino)propyl, 4-(methylamino)butyl, and 4-(dimethylamino)butyl, and particularly preferred examples include 2-(methylamino)ethyl, and 3-(methylamino)propyl.
  • a lower alkyl group substituted with an alkoxy group is also preferred.
  • the lower alkoxy group include linear or branched alkoxy having 1 to 4 carbon atoms. Specific examples include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group and the like, and methoxy group, and ethoxy group are preferred.
  • the lower alkyl group may be substituted with one or more lower alkoxy groups, and a lower alkyl group substituted with one alkoxy group is generally preferred.
  • Preferred examples include 2-methoxyethyl, 3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, and 4-methoxybutyl, and 2-methoxyethyl, and 3-methoxypropyl are particularly preferred.
  • a 8 a lower alkyl group substituted with an acylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more acylamino groups, and a lower alkyl group substituted with one acylamino group is generally preferred.
  • acylamino group examples include an alkylcarbonylamino group, and an arylcarbonylamino group ("alkyl” and “aryl” herein referred to are the same as those described above).
  • alkyl and aryl herein referred to are the same as those described above.
  • a lower alkyl group substituted with an alkylcarbonylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more alkylcarbonylamino groups, and a lower alkyl group substituted with one of alkylcarbonylamino group is generally preferred.
  • Specific examples include acetylaminomethyl, 2-(acetylamino)ethyl, 3-(acetylamino)propyl, 4-(acetylamino)butyl, propionylaminomethyl, 2-(propionylamino)ethyl, 3-(propionylamino)propyl, 4-(propionylamino)butyl and the like.
  • a lower alkyl group substituted with an arylcarbonylamino group is also preferred.
  • the lower alkyl group may be substituted with one or more arylcarbonylamino groups, and a lower alkyl group substituted with one of arylcarbonylamino group is generally preferred. Specific examples include benzoylaminomethyl, 2-(benzoylamino)ethyl, 3-(benzoylamino)propyl, 4-(benzoylamino)butyl and the like.
  • a cycloalkyl group is also preferred. The cycloalkyl is the same as that described above.
  • a lower cycloalkyl group is preferred, and particularly preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • an aryl group is also preferred. The aryl is the same as that described above, and preferred examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
  • an aromatic heterocyclic group is also preferred. The aromatic heterocyclic group is the same as that described above, and specific examples include, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl and the like.
  • a 71 and A 8 together become an alkylene group, -alkylene-O-alkylene-, -alkylene-NH-alkylene-, or -alkylene-N(alkyl)-alkylene- to form a ring (the alkylene moiety mentioned above may be substituted with an alkyl group).
  • the alkyl group is preferably a lower alkyl group, and examples of the lower alkyl group include, methyl, and ethyl. More preferred examples include methyl.
  • the ring formed by A 71 and A 8 combined together to become alkylene is preferably a 4- to 7-membered ring, and particularly preferred examples include 4-, 5-, and 6-membered rings.
  • the ring formed by A 71 and A 8 combined together to become -alkylene-O-alkylene-, -alkylene-NH-alkylene-, or -alkylene-N(alkyl)-alkylene- is preferably a 6- or 7-membered ring.
  • a 71 and A 8 do not combine together to form a ring.
  • Groups in each of one or more combinations selected from the group consisting of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 may bind to each other to form a 5- or 6-membered ring, particularly preferably a 6-membered ring. In this group, it is particularly preferred that one 5- or 6-membered ring is formed with one of the aforementioned combinations.
  • the ring is preferably consists of carbon atoms except for the N atom to which A 3 binds.
  • a 11 and A 21 are preferably hydrogen atoms, and the ring is most preferably a saturated ring.
  • Y is a single bond
  • Z is -N(A 6 )(A 61 )
  • Y is -CH(A 3 )-
  • Z is -N(A 6 )(A 61 )
  • Y is -CH(A 3 )-C(A 4 )(A 41 ), and Z is -N(A 6 )(A 61 ), it is preferred that, for example, the groups of A 2 and A 3 bind to each other to form a 6-membered ring.
  • examples of the structure represented by the formula (2): [the bond on the left of Y binds to N (nitrogen atom) bonding to X 2 ], which is a partial structure in the formula (1), wherein a ring is formed with the aforementioned combinations, include the followings structures containing a 5- or 6-membered ring, i.e., groups represented by the formula, (2-1), formula (2-2), formula (2-3), formula (2-4-t), formula (2-4-c), formula (2-5-t), formula (2-5-c), formula (2-6-t), formula (2-6-c), and formula (2-7).
  • a 6 represents hydrogen atom, or an alkyl group
  • a 61 represents hydrogen atom, an alkyl group, an alkyl group substituted with an aryl group, an alkyl group substituted with an aromatic heterocyclic group, an alkyl group substituted with carboxyl group, an alkyl group substituted with cyano group, an alkyl group substituted with hydroxyl group, an alkyl group substituted with an alkoxy group, an alkyl group substituted with a substituted alkoxy group, an alkyl group substituted with amino group, an alkyl group substituted with an alkylamino group, an alkyl group substituted with aminocarbonyl group, an alkyl group substituted with an alkylaminocarbonyloxy group, an alkyl group substituted with a cycloalkylaminocarbonyloxy group, an alkyl group substituted with an arylaminocarbonyloxy group, an alkyl group substituted with mercapto group, an alkyl
  • the bonds in the cyclohexane ring are in the trans-conformation in the groups represented by the formula (2-4-t), formula (2-5-t), and formula (2-6-t), or cis-conformation in the groups represented by the formula (2-4-c), formula (2-5-c), and formula (2-6-c).
  • the groups represented by the formula (2-1), formula (2-2), formula (2-4-t), formula (2-4-c), and formula (2-7) are preferred, and the groups represented by the formula (2-1), formula (2-2), formula (2-4-t), and formula (2-7) are particularly preferred.
  • Preferred examples also include either one of or a combination of any two of these groups.
  • Preferred examples of A 6 and A 61 are as mentioned above.
  • the compounds of the present invention represented by the formula (1) may have one or more asymmetric carbons, and stereoisomers based on such asymmetric carbons such as optical antipodes and diastereoisomer may exist.
  • the compounds of the present invention may have an olefinic double bond or a cyclic structure, two or more kinds of stereoisomers may exist, and such stereoisomers in pure forms, any mixtures and the like of such stereoisomers all fall within the scope of the present invention.
  • the compounds of the present invention represented by the formula (1) may exist as tautomers. Existence of such tautomers is apparent to those skilled in the art, and such tautomers all fall within the scope of the present invention.
  • the compounds of the present invention may also exist as salts.
  • Forms of the salts are not particularly limited. Acid addition salts are generally formed, or base addition salts may be formed depending on the types of substituents.
  • the types of physiologically acceptable salts are well known to those skilled in the art, and examples include, for example, those described by Berge et al. in J. Pharm. Sci., 66, 1-19 (1977) .
  • acid addition salts include, for example, mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, and hydrogensulfates, phosphates, hydrogenphosphates, organic acid salts such as acetates, trifluoroacetates, gluconates, lactates, salicylates, citrates, tartrates, ascorbates, succinates, maleates, fumarates, formates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates and p-toluenesulfonates.
  • mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, and hydrogensulfates
  • phosphates hydrogenphosphates
  • organic acid salts such as acetates, trifluoroacetates, gluconates, lactates, salicylates
  • Suitable pharmacologically acceptable base addition salts include, for example, metal salts such as sodium salts, potassium salts, magnesium salts, lithium salts, calcium salts, aluminum salts and zinc salts, and salts of organic amines such as ethanolamine.
  • Methods for preparation of the compounds represented by the formula (1) are not particularly limited. For example, they can be prepared according to the methods described below (Preparation methods 1 to 4).
  • the PG 1 group used herein is not particularly limited so long that the group can protect hydroxyl group, does not react in reactions in this preparation process other than the deprotection step, and further can be easily removed.
  • Preferred examples of the protective group of hydroxyl group include a trialkylsilyl group such as tert-butyldimethylsilyl group (TBDMS group), an acyl group such as acetyl group, benzyl group (Bn group), and tetrahydropyranyl (THP) group, and particularly preferred examples include Bn group and THP group.
  • the PG 2 group is not particularly limited so long that the group can protect amino group, does not react in reactions in this preparation process other than the deprotection step, and further can be easily removed.
  • Preferred examples include t-butoxycarbonyl group (Boc group), benzyloxycarbonyl group (Cbz group), benzyl group (Bn group), phthaloyl group, and triphenylmethyl group, and particularly preferred examples include Boc group, Cbz group, and Bn group.
  • the PG 3 group is not particularly limited so long that the group can protect carboxyl group, does not react in reactions in this preparation process other than the deprotection step, and further can be easily removed. Examples include alkyl groups, and specifically, tert-butyl group is preferred, for example.
  • the PG 4 group is not particularly limited so long that the group can protect mercapto group, does not react in reactions in this preparation process other than the deprotection step, and further can be easily removed.
  • Preferred examples include an acyl group such as acetyl group (Ac group), benzyl group (Bn group), triphenylmethyl group, methoxymethyl group, and tetrahydropyranyl group (THP group), and particularly preferred examples include Ac group, and THP group.
  • a method of preparing the compounds of the formula (1) by removing Bn group from a compound of the formula (A) wherein PG 1 represents Bn group can be performed by using known reduction conditions of hydrogenation.
  • the method include a method performed in an alcohol, ethyl acetate, an ether solvent such as 1,4-dioxane, or a mixed solvent thereof, and examples of catalyst include, for example, palladium/carbon.
  • the reaction include a method of performing the reaction at 0 to 80°C, preferably 10 to 40°C.
  • examples of a method of preparing the compounds of the formula (1), by removing THP group from a compound of the formula (A) wherein PG 1 represents THP group include a method utilizing acidolysis.
  • the acid include mineral acids, and specific examples are hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, and hydrochloric acid is preferred.
  • the acid is preferably used in an amount of 1 to 100 fold moles.
  • examples of the solvent include water, alcohols, ether type solvents such as 1,4-dioxane, and mixed solvents thereof.
  • the reaction is preferably performed in the temperature range of from room temperature to reflux temperature of the solvent.
  • a method of preparing the compounds of the formula (1) by removing Boc group from a compound of the formula (A) wherein PG 2 represents Boc group can be performed by using known acidic conditions.
  • the solvent used for the reaction the reaction can be performed, for example, without solvent, or in water, an alcohol, acetonitrile, an ether solvent such as 1,4-dioxane, or a mixed solvent thereof.
  • the acid a mineral acid and organic acid can be used. Specific examples include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfonic acid, phosphoric acid and the like, and hydrochloric acid is preferred.
  • the acid is preferably used in an amount of 1 to 100 fold moles based on the compound of the formula (A).
  • the reaction is preferably performed in the temperature range of from room temperature to the reflux temperature of the solvent.
  • the removal of Boc group can be performed by using trifluoroacetic acid. Examples of this method include a method of using trifluoroacetic acid alone, and a method of using trifluoroacetic acid as a mixed solvent system with water or dichloromethane.
  • the reaction is performed, for example, in the temperature range of from 0 to 100°C, preferably from room temperature to 50°C.
  • the amount of trifluoroacetic acid 1 to 100 fold moles are preferably used based on the compound of the formula (A).
  • the method of preparing the compounds of the formula (1) by removing Cbz group (or Bn group) from a compound of the formula (A) wherein PG 2 represents Cbz group or Bn group can be performed by using known reduction conditions of hydrogenation.
  • the method include a method performed in an alcohol, ethyl acetate, an ether type solvent such as 1,4-dioxane, or a mixed solvent thereof, and examples of catalyst include, for example, palladium/carbon.
  • the reaction is performed, for example, at 0 to 100°C, preferably 10 to 80°C.
  • the method of preparing the compounds of the formula (1) by removing tert-butyl group from a compound of the formula (A) wherein PG 3 represents tert-butyl group can be performed by known acidolysis.
  • the acid include mineral acids. Specific examples include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, and hydrochloric acid is preferred.
  • the amount of the acid used it is preferable to use 1 to 100 fold moles.
  • the solvent used for the reaction include, for example, water, alcohols, ether solvents such as 1,4-dioxane and mixed solvents thereof, and 1,4-dioxane is preferred.
  • the reaction is preferably performed in the temperature range of from room temperature to the reflux temperature of the solvent.
  • the method of preparing the compounds of the formula (1) by removing Ac group form a compound of the formula (A) wherein PG 4 represents Ac group can be performed by a known decomposition method using aqueous alkali or aqueous ammonia.
  • the alkali include, for example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide and the like, and sodium hydroxide is preferred.
  • the concentration of the aqueous alkali is, for example, 0.001 to 5 N, preferably 0.05 to 3 N.
  • the concentration of aqueous ammonia is preferably, for example, 1 to 30%.
  • Examples of the solvent used for the reaction include, for example, water, an alcohol, an ether type solvent such as tetrahydrofuran, and 1,4-dioxane, and a mixed solvent of these, and a mixed solvent of water and methanol is preferred.
  • the reaction is preferably performed at a temperature in the range of from 0°C to the reflux temperature of the solvent.
  • examples of the method of preparing the compounds of the formula (1) by removing THP from a compound of the formula (A) wherein PG 4 represents the THP group include known decomposition methods using aqueous silver nitrate (see, for example, G.F. Holland, L.A. Cohen, J. Am. Chem.
  • one or more kinds of these protective groups may be introduced into the compound of the formula (A) as the case may be, and when two or more protective groups exist, it is also preferable to carry out deprotection with a combination of the methods mentioned for Step 1-1.
  • Z a represents the same group as that represented by Z in the general formula (1), such compounds of the formula (A) constitute a part of the compounds of the formula (1), and thus Step 1-1 mentioned above is unnecessary.
  • the compounds of the formula (A-2) can be prepared by dehydrogenation of a compound of the formula (A-1) in an inert solvent (Step 1-1-1).
  • the catalyst for example, palladium catalysts such as 5% palladium/carbon, 10% palladium/carbon, or palladium black, and sulfur are preferred.
  • the inert solvent include xylene, mesitylene, toluene and the like, and xylene is preferred.
  • the reaction temperature is 60°C or higher, preferably 120 to 150°C.
  • the substituents on the aromatic ring of the compound of the formula (1), R 1 , R 5 , R 6 , R 7 , and R 8 can be introduced depending on the type thereof by a suitable combination of known reactions, for example, electrophilic substitution reactions such as halogenation and nitration, subsequent conversion of nitro group into amino group by reduction, conversion of amino group into a halogen atom, hydroxyl group, or the like, and conversion of a halogen atom into an alkyl group, an alkenyl group, an aryl group, amino group, an alkylamino group, an arylamino group, hydroxyl group, an alkoxyl group, or the like.
  • electrophilic substitution reactions such as halogenation and nitration
  • subsequent conversion of nitro group into amino group by reduction conversion of amino group into a halogen atom, hydroxyl group, or the like
  • the compounds of the formula (A-1) mentioned above can be classified into the following two types of compounds, depending on the types of R 1 , R 5 , R6, R 7 , and R 8 ; Specifically, i) compounds represented by the following formula (A-a): [wherein Y, A 1 , A 11 , A 2 , A 21 , Z a , R 6 , R 7 , R 8 , and X 1 -X 2 have the same meanings as those defined above], which correspond to the compounds of the formula (A-1) wherein R 1 , and R 5 are hydrogen atoms, and ii) compounds represented by the following formula (A-d): [wherein Y, A 1 , A 11 , A 2 , A 21 , Z a , R 1 , R 5 , and X 1 -X 2 have the same meanings as those defined above], which correspond to the compounds of the formula (A-1) wherein R 6 , R 7 , and R 8 are hydrogen atoms.
  • the compounds of the aforementioned formula (A-a) can be prepared, for example, as follows. Specifically, the compounds can be prepared by deprotecting (corresponding to the deprotection for the protective group of amino group in Step 1-1) a compound of the following formula (A-a-1): [wherein Y, A 1 , A 11 , A 2 , A 21 , R 6 , R 7 , R 8 , and X 1 -X 2 have the same meanings as those defined above, Z b is -N(A 6 )(PG 2 ), and A 6 and PG 2 have the same meanings as those defined above], which corresponds to a compound of the formula (A-a) wherein Z a is -N(A 6 )(PG 2 ), to prepare a compound of the following formula (A-a-2): [wherein Y, A 1 , A 11 , A 2 , A 21 , X 1 -X 2 , R 6 , R 7 , and R 8 have the same meanings as those defined
  • W in A 62 -W used for the preparation of a compound of the formula (A-a) wherein Z a is -NH(A 6 ) from a compound of the formula (A-a-2) is not particularly limited so long as W is a leaving group.
  • Examples include, for example, a halogen atom, an alkylsulfonyloxy group, and an arylsulfonyloxy group, preferred examples include chlorine atom, bromine atom, iodine atom, methanesulfonyloxy group, and p-toluenesulfonyloxy group, particularly preferred examples are chlorine atom, bromine atom, and iodine atom, and still more particularly preferred examples are chlorine atom, and bromine atom.
  • Conditions of the reaction for preparing the compounds of the formula (A-a) wherein Z a is -N(A 6 )(A 62 ) from a compound of the formula (A-a-2) are as follows.
  • the reaction is usually performed in the presence of a base, and a mineral base is preferred.
  • a mineral base examples include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium hydroxide, and potassium carbonate is particularly preferred.
  • the compound represented as A 62 -W is preferably used in an amount of 1 fold mole or more, particularly preferably 2 to 10 fold moles, based on the compound of the aforementioned formula (A-a-2).
  • an inert solvent for example, an alcoholic solvent such as methanol and ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, sulfolane, tetrahydrofuran, 1,4-dioxane, acetone, 2-butanone, dimethyl sulfoxide, acetonitrile and the like can be used alone, or as a mixed solvent thereof, and water, dimethylformamide and acetone are preferred.
  • the reaction temperature is, for example, -10°C or higher, preferably 10 to 40°C.
  • the reaction time is, for example, usually 0.5 hour or more, preferably 2 to 10 hours.
  • Examples of the acylation reagent include carboxylic acid chlorides, carboxylic acid anhydrides, carboxylic acid active esters, carboxylic acids and the like.
  • Examples of acetylation reagent include, for example, acetyl chloride, acetic anhydride, acetic acid active esters, acetic acid and the like.
  • Examples of the carboxylic acid active esters include carboxylic acid succinimides, imidazole carboxylates, carboxylic acid 4-nitrophenyl esters, carboxylic acid pentafluorophenyl esters and the like.
  • the acylation reagent is usually used preferably in an amount of 1 or more fold moles, most preferably 1.1 to 10 fold moles, based on the compound of the aforementioned formula (A-b).
  • a carboxylic acid is directly used as the acylation reagent, it is usually preferable to perform the reaction in the presence of a dehydration condensing agent.
  • dehydration condensing agent examples include N,N-dicyclohexylcarbodiimide, N,N-diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-chloro-1-methylpyridinium iodide, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), benzotriazol-1-yl
  • the acylation reaction is also preferably performed, for example, in the presence of an additive such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-nitrophenol (HONp) and pentafluorophenol (HOPfp).
  • an additive such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), 4-nitrophenol (HONp) and pentafluorophenol (HOPfp).
  • HOBt 1-hydroxybenzotriazole
  • HOAt 1-hydroxy-7-azabenzotriazole
  • HSu N-hydroxysuccinimide
  • HONp 4-nitrophenol
  • pentafluorophenol pentafluorophenol
  • the acylation reaction is also preferably performed, for example, in the presence of an organic tertiary amine such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium hydroxide.
  • an organic tertiary amine such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene
  • an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium hydroxide.
  • the amount of the base preferably 0.01 to 10 fold moles or more, most
  • an inert solvent for example, water, an alcoholic solvent such as tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrolidone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, benzene, toluene, ethyl acetate, dimethyl sulfoxide, sulfolane, acetonitrile, or the like can be used as each kind, or a mixed solvent thereof.
  • the reaction temperature is, for example, -10°C or higher, preferably 10 to 40°C.
  • the reaction time is, for example, usually 0.5 hour or more, preferably 2 to 10 hours.
  • the compounds of the formula (A-a) wherein A 62 is "an alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 )" [wherein -X 3 - represents carboxyl group], and A 7 and A 71 together become an alkylene group, or an alkylene group substituted with an alkyl group to form a ring can be prepared in the same manner as Step 1-2-2 by reacting the "compound of the formula (A-b) wherein A 7 is hydrogen atom" obtained above as a starting material with a compound represented as (PG 3 )O-X 3 -A 72 [wherein PG 3 has the same meaning as defined above, -X 3 - is carbonyl group, and A 72 represents an alkyl group of which end is substituted with a leaving group (the alkyl group may be substituted with another alkyl group)], then removing PG 3 by the aforementioned known method, and cyclizing the resultant using a dehydration condens
  • the sulfonylation reagent examples include sulfonyl chloride and sulfonic acid anhydride, and sulfonic acid anhydride is particularly preferred.
  • Preferred examples of the base include an organic tertiary amine such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene, and an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium hydroxide.
  • the amount of the base is preferably 0.01 to 10 fold moles or more, particularly preferably 0.1 to 5 fold moles.
  • an inert solvent for example, water, an alcoholic solvent such as tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrolidone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, benzene, toluene, ethyl acetate, dimethyl sulfoxide, sulfolane, acetonitrile, or the like can be used independently, or a mixed solvent thereof.
  • the reaction temperature is, for example, -10°C or higher, preferably 10 to 40°C.
  • the reaction time is, for example, usually 0.5 hour or more, preferably 2 to 10 hours.
  • Example of the reagent used for preparing the active ester include 4-nitrophenyl chloroformate, 4-nitrophenyl carbonate, 1,1'-carbonyldiimidazole and the like, and preferred examples include 4-nitrophenyl chloroformate.
  • the active esterification regent is preferably used in an amount of 1 fold mole or more, particularly preferably 1.1 to 10 fold moles, based on the compound of the formula (A-b) mentioned above.
  • the acylation reaction is also preferably performed, for example, in the presence of an organic tertiary amine such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene, or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium hydroxide.
  • an organic tertiary amine such as triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and 1,8-diazabicyclo[5.4.0]undec-7-ene
  • an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydroxide, and sodium hydroxide.
  • the amount of the base preferably 0.01 to 10 fold moles or more, most
  • an inert solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrolidone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform, benzene, toluene, dimethyl sulfoxide, sulfolane, acetonitrile, or the like can be used independently, or as a mixed solvent thereof.
  • the reaction temperature is, for example, -10°C or higher, preferably 10 to 40°C.
  • the reaction time is, for example, usually 0.5 hour or more, preferably 2 to 10 hours.
  • the target compound can be prepared by successively reacting the active ester prepared as described above with an alcohol or amine suitably corresponding to an target compound to be prepared under the same conditions as mentioned above.
  • the compounds of the formula (A-a) wherein Z a is -N(A 6 )(A 62 ), and A 62 is an alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 ) [where -X 3 - represents -C( S)-N(A 8 )-, and A 7 , and A 71 have the same meanings as those defined above, provided that a compound where A 7 and A 71 combine together to become an alkylene group, or an alkylene group substituted with an alkyl group to form a ring, or A 71 and A 8 combine together become an alkylene group, -alkylene-O-alkylene-, -alkylene-NH-alkylene-, or -alkylene-N(alkyl)-alkylene- to form a ring is excluded] can be prepared by deriving a compound of the formula (A-b) into an active ester using 1,1'-thiocarbony
  • the compounds of the formula (A-a) wherein Z a is -N(A 6 )(A 62 ), and A 62 is "an alkyl group of which end is substituted with an alkylaminocarbonyloxy group, an alkyl group substituted with a cycloalkylaminocarbonyloxy group, or an alkyl group substituted with an arylaminocarbonyloxy group" can be prepared from a compound of the formula (A-a) wherein Z a is an alkyl group substituted with hydroxyl group in the same manner as that of Steps 1-2-6 and 1-2-7.
  • the compounds can be prepared by allowing a regent such as 4-nitrophenyl chloroformate, 4-nitrophenyl carbonate, or 1,1'-carbonyldiimidazole to react on a compound of the formula (A-a) wherein Z a is an alkyl group substituted with hydroxyl group to convert the compound into an active ester, and successively reacting the active ester with an alkylamine, cycloalkylamine, or arylamine suitably corresponding to an target compound to be prepared (Steps 1-2-9).
  • a regent such as 4-nitrophenyl chloroformate, 4-nitrophenyl carbonate, or 1,1'-carbonyldiimidazole
  • the compounds of the formula (A ⁇ a ⁇ 1) mentioned above can be prepared from a compound of the following formula (A-c) : [wherein Y, A 1 , A 11 , A 2 , A 21 , Z b , and X 1 -X 2 have the same meanings as those defined above], which corresponds to a compound of the formula (A-a-1) wherein R 6 , R 7 , and R 8 are hydrogen atoms, for example, as follows.
  • Preferred examples of the inert solvent include N,N-dimethylformamide.
  • Examples of the method include a method of using the halogenation regent in an amount of 1 fold mole or more, preferably 1 to 10 fold moles, based on the compound of the formula (A-c).
  • Examples of the method include a method of performing the reaction at a reaction temperature of -10 to 120°C, preferably about 0 to 80°C.
  • the compounds represented by the following formula (A-i): [wherein Y, A 1 , A 11 , A 2 , A 21 , Z b , and X 1 -X 2 have the same meanings as those defined above] can be obtained by reducing the nitro group of the compound of the formula (A-h) obtained as described above with hydrogen in a solvent, for example, an alcohol such as methanol and ethanol, an ether such as tetrahydrofuran and 1,4-dioxane, water, ethyl acetate, or the like, used independently, or in a solvent consisting of a suitable combination of these in the presence of a base such as triethylamine, N,N-diisopropylethylamine, and pyridine, and a platinum group catalyst such as palladium/carbon, palladium black, palladium hydroxide, platinum oxide, and platinum black (Step 1-5).
  • a solvent for example, an alcohol such as methanol and ethanol,
  • Preferred examples of the method for this reaction include a method of performing the reaction in the presence of triethylamine in an amount of 1 to 3 fold moles and 1 to 50% by weight of palladium/carbon catalyst in a methanol solvent at a temperature of 10 to 80°C under a hydrogen atmosphere of ordinary pressure to 3 atmospheres.
  • Steps 1-3 to 1-5 can be performed by referring to known literatures (for example, Kucznierz, R., Dickhaut, J, Leinert, H., Von Der Saal, W., Synth. Commun., 29, 1617 (1999 ); Ping Chen, Bioorganic & Medicinal Chemistry Letters, 13, 1345 (2003 )).
  • the compounds represented by the following formula (A-i) obtained as described above can be subjected to, for example, a known diazotization-Sandmeyer reaction (see, for example, Denny, William., et al, J. Med. Chem., 2002, 740 ; Kulka, J. Am. Chem. Soc., 75, 3597 (1953 ) and the like) to obtain the compounds represented by the following formula (A-j): [wherein Y, A 1 , A 11 , A 2 , A 21 , Z b , and X 1 -X 2 have the same meanings as those defined above, and R 62 is a halogen atom].
  • the compounds of the formula (A-a-1) mentioned above can be prepared ("coupling method using catalyst”). Hydroxyl group can also be prepared by dealkylating an alkoxyl group according to a known method.
  • the compounds of the formula (A-a-1) obtained above can be converted into the compounds represented by the formula (A-a) as described above. For example, the conversion can be performed by any of Steps 1-2-1, 1-2-2, 1-2-2-1, 1-2-3, 1-2-4, 1-2-5, 1-2-6, 1-2-7, 1-2-8, and 1-2-9, or an arbitrary combination of these.
  • the compounds of the formula (A-d) mentioned above can be prepared as follows.
  • the compounds of the formula (A-d) wherein Z a is -N(A 6 )(A 62 ) can be prepared by deprotecting (corresponding to the deprotection of protective group of amino group in Step 1-1) a compound of the following formula (A-c-1): [wherein Y, A 1 , A 11 , A 2 , A 21 , R 1 , R 5 , Z b , and X 1 -X 2 have the same meanings as those defined above], which corresponds to a compound of the formula (A-d) wherein Z a is -N(A 6 )(PG 2 ), to prepare a compound of the following formula (A-d-1): [wherein Y, A 1 , A 11 , A 2 , A 21 , R 1 , R 5 , Z c , and X 1 -X 2 have the same meanings as those defined above], which corresponds to a compound of the
  • the compounds of the following formula (A-e): [wherein Y, A 1 , A 11 , A 2 , A 21 , R 1 , R 5 , Z d , and X 1 -X 2 have the same meanings as those defined above], which correspond to the compounds of the formula (A-d) wherein Z a in the formula (A-d) is -N(A 6 )(A 63 ), can be prepared by, for example, reacting a compound of the formula (A-d-1) with a compound represented as A 63 -W [wherein A 63 and W have the same meaning as defined above] (Step 1-7-2-1). This step can be performed in the same manner as that of Step 1-2-2-1 mentioned above.
  • the compounds of the formula (A-d) wherein Z a is -N(A 6 )(A 62 ), and A 62 is an alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 ) can be prepared by, for example, the same methods as those of Steps 1-2-3 to 1-2-8 (Steps 1-7-3 to 1-7-8, respectively).
  • the compounds of the formula (A-d) wherein Z a is -N(A 6 )(A 62 ), and A 62 is an alkyl group of which end is substituted with an alkylaminocarbonyloxy group, an alkyl group substituted with a cycloalkylaminocarbonyloxy group, or an alkyl group substituted with an arylaminocarbonyloxy group can be prepared from a compound of the formula (A-d) wherein Z a is an alkyl group substituted with hydroxyl group, for example, in the same manner as that of Step 1-2-9 mentioned above (Step 1-7-9).
  • the compounds represented by the formula (A-c-1) can be prepared by subjecting a compound represented by the following formula (A-k): [wherein Y, A 1 , A 11 , A 2 , A 21 , Z b , and X 1 -X 2 have the same meanings as those defined above, and R 11 , and R 51 are hydrogen atoms, or independently represent hydrogen atom, or a halogen atom] to the aforementioned "coupling method using catalyst".
  • the compounds of the formula (A-c-1) wherein R 11 , and R 51 independently represent hydrogen atom, or hydroxyl group can also be prepared by hydrolyzing a compounds of the formula (A-k) wherein R 11 , and R 51 independently represent hydrogen atom, or a halogen atom in a mineral acid (Step 1-8).
  • the mineral acid include hydrochloric acid, sulfuric acid, nitric acid, and perchloric acid, and preferred examples include hydrochloric acid.
  • the reaction temperature is, for example, -10 to 150°C, preferably 20 to 120°C.
  • the compounds of the formula (A-c) mentioned above constitute a part of the compounds of the formula (A-k), and in this case, R 11 , and R 51 represent hydrogen atom.
  • the compounds represented by the formula (A-k) can be prepared by cyclizing a compound represented by the following formula (B): [wherein Y, A 1 , A 11 , A 2 , A 21 , Z b , and X 1 -X 2 have the same meanings as those defined above, amd R 1 , and R 5 independently represent hydrogen atom, or a halogen atom] (Step 1-9).
  • Examples of the cyclization method include a method of performing the cyclization in the presence of a phosphorus reagent and an azo compound, and a method of reacting the compound with an alkylsulfonyl chloride, an arylsulfonyl chloride, an alkylsulfonic acid anhydride or an arylsulfonic acid anhydride in the presence of a base, and a preferred method is a method of performing the cyclization in the presence of a phosphorus reagent and an azo compound in an inert solvent (see, for example, Tsunoda et al., Chemistry Letters, 539 (1994 ); or Mitsunobu, 0., Synthesis, 1 (1981)).
  • Examples of the inert solvent include, for example, tetrahydrofuran, toluene, and dichloromethane, and a preferred example is tetrahydrofuran.
  • Examples of the phosphorus reagent include, for example, triphenylphosphine, and tri(n-butyl)phosphine.
  • Example of the azo compound include, for example, diethyl azodicarboxylate, di(iso-propyl) azodicarboxylate, and 1,1'-azobis(N,N-dimethylformamide).
  • Each of the phosphorus reagent and the azo compound may be the same or different, and is used in an amount of 1 fold mole or more, preferably 2 to 4 fold moles, based on the compound of the formula (B).
  • the reaction temperature is, for example, -10°C or higher, preferably about 0 to 60°C.
  • a compound of the formula (C) can be hydroborated with a boron reagent, then oxidized and hydrolyzed to obtain the compound.
  • a boron reagent examples include dicyclohexylborane, disyamyl borane, thexyl borane, catechol borane, 9-borabicyclo[3.3.1]nonane (9-BBN) dimer, 9-BBN monomer and the like, and 9-BBN dimer, and 9-BBN monomer are preferred.
  • the boron reagent is preferably used in an amount of usually 1 fold mole or more, preferably about 2 to 5 fold moles.
  • the solvent examples include ether type solvents such as tetrahydrofuran and 1,4-dioxane and the like, and tetrahydrofuran is preferred.
  • the reaction temperature is 0°C to the boiling temperature of the solvent used, preferably 10 to 60)°C.
  • the reaction time is 2 hours or more, preferably 10 to 20 hours.
  • examples of the oxidizing agent include 30% aqueous hydrogen peroxide, sodium peroxoborate, N-methylmorpholine N-oxide, triethylamine N-oxide and the like, and 30% aqueous hydrogen peroxide, and sodium peroxoborate are preferred.
  • the oxidizing agent is used in an amount of, for example, 1 fold mole or more, preferably 2 to 20 fold moles.
  • the reaction time is, for example, 0.25 to 10 hours, preferably 0.5 to 4 hours.
  • the hydrolysis is performed under an alkaline condition, and examples of the alkali include aqueous sodium hydroxide, aqueous potassium hydroxide and the like.
  • the alkali is used in an amount of, for example, usually 2 to 100 fold moles, preferably 3 to 20 fold moles, and the reaction time is, for example, 2 hours or more, preferably 2 to 4 hours.
  • the compounds of the formula (C) can be prepared by allowing a reducing agent to react on a compound of the formula (D) and a compound of the formula (E) in a solvent, for example, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, and chloroform, an ether such as 1,4-dioxane and tetrahydrofuran, an alcohol such as methanol, ethanol, and isopropanol, benzene, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetic acid and the like independently used, or a mixed solvent consisting of a suitable combination of these.
  • a solvent for example, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, and chloroform, an ether such as 1,4-dioxane and tetrahydrofuran, an alcohol
  • the reducing agent examples include a metal hydride reducing agent such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane/tetrahydrofuran complex, borane/pyridine complex, borane/triethylamine complex, borane/dimethyl sulfide complex, and lithium triethylborohydride, and a preferred example is sodium triacetoxyborohydride.
  • the reducing agent is used in an amount of, for example, 0.5 fold mole or more, preferably 1 to 20 fold moles.
  • the reaction temperature is, for example, 0°C or higher, preferably 10 to 80°C.
  • the reaction time is, for example, 0.1 hour or more, preferably 0.3 to 48 hours.
  • Preferred examples of the method include a method of performing the reduction by a known method under a hydrogen gas atmosphere in the presence of a platinum group catalyst, such as palladium/carbon, palladium hydroxide, platinum oxide, and platinum black.
  • the compounds of the formula (D) can be prepared from i) a compound represented by the following formula (F-a): [wherein X has the same meanings as that defined above], or ii) a compound represented by the following formula (F-b): [wherein R 12 , and R 52 independently represent hydrogen atom, or a halogen atom (chlorine atom, bromine atom, iodine atom and the like, preferably chlorine atom), and X has the same meaning as that defined above].
  • a known reduction reaction of nitro group can be used. This reduction is preferably carried out in an inert solvent.
  • the inert solvent include alcohols, ethers, and esters, preferred examples include esters, and especially preferred examples include ethyl acetate.
  • the reduction reagent include tin (divalent) reagents. Preferred examples of the tin (divalent) reagents include stannous chloride, and hydrate thereof.
  • the reaction temperature is, for example, -20°C or higher, preferably 10 to 50°C.
  • the reaction time is, for example, 2 hours or more, preferably 4 to 15 hours.
  • the compounds of the formula (F-b) can be prepared by allowing a halogenation regent to react on a compound of the following formula (F-c): [wherein X has the same meaning as that defined above] for halogenation (Step 1-13).
  • the halogenation reagent include phosphorous oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxybromide, phosphorus tribromide, phosphorus pentabromide and the like, and preferred examples include phosphorous oxychloride.
  • the halogenation reagent is preferably used in an amount of 0.1 fold mole or more, particularly preferably 1 to 10 fold moles, based on the compound of the formula (F-c).
  • examples of the method include a method of performing the reaction without solvent, or in an inert solvent, and preferred examples of the method include a method of performing the reaction without solvent, or using dichloromethane, 1,2-dichloroethane, chloroform, or toluene as the solvent.
  • the reaction is preferably performed at room temperature or a higher temperature.
  • the compounds of the formula (F-c) can be prepared by oxidizing a compound of the formula (F-a) (Step 1-14).
  • oxidizing agent include aqueous hydrogen peroxide, sodium periodate, sodium perborate, 3-chloroperbenzoic acid, ruthenium trichloride, and dimethyldioxirane, and preferred examples include 3-chloroperbenzoic acid.
  • the oxidizing agent is preferably used in an amount of 0.1 fold mole or more, particularly preferably 1 to 20 fold moles, based on the compound of the formula (F-a).
  • the solvent examples include acetic acid, trifluoroacetic acid, dichloromethane, 1,2-dichloroethane, chloroform, acetonitrile, acetone, trichlorofluoromethane, benzene, 1,4-dioxane, tert-butanol, water, and mixed solvents of these, and preferred examples include chloroform.
  • the compounds represented of the formula (F-a) can be prepared by reacting known 4-bromo-5-nitroisoquinoline (Reference Example 1) with a tin compound represented by the following formula (G): [Formula 28].
  • X-SnBu 3 (G) [wherein X has the same meaning as defined above, and Bu represents n-butyl] (Step 1-15).
  • Examples of the tin compound represented by the formula (G) include those commercially available and those known from literatures (see, for example, Seyferth et al., Chem. Ind., 402 (1959 ); J. Amer. Chem. Soc., 361 (1962 ); and J. Amer. Chem. Soc., 515 (1957 )).
  • the amount of this tin compound is, for example, 1 fold mole or more, preferably 1 to 3 fold moles, based on the compound of the formula (E).
  • the first reaction condition corresponds to a method of performing the reaction in toluene or an ether type solvent in the presence of tetrakis(triphenylphosphine)palladium(0) as a catalyst, and 2,6-di(tert-butyl)-4-cresol (BHT) as a polymerization inhibitor.
  • tetrakis(triphenylphosphine)palladium(0) is used in an amount of, for example, 0.001 fold mole or more, preferably 0.01 to 0.2 fold mole
  • BHT is used in an amount of, for example, 0.001 fold mole or more, preferably 0.005 to 0.01 fold mole.
  • the solvent toluene or 1,4-dioxane is preferred, and the reaction temperature is, for example, 10°C or higher, preferably 80 to 120°C.
  • the second reaction condition corresponds to a method of performing the reaction in an ether type solvent in the presence of a palladium compound such as tetrakis(triphenylphosphine)palladium(O), palladium(II) acetate, or tris(dibenzylideneacetone)dipalladium(O), or a phosphorus compound such as triphenylphosphine or tri(tert-butyl)phosphine, and cesium fluoride as an additive.
  • a palladium compound such as tetrakis(triphenylphosphine)palladium(O), palladium(II) acetate, or tris(dibenzylideneacetone)dipalladium(O)
  • a phosphorus compound such as triphenylphosphine or tri(tert-butyl)phosphine
  • cesium fluoride as an additive.
  • the palladium compound tris(dibenzylideneacetone
  • the solvent is preferably 1,4-dioxane.
  • the palladium compound is used in an amount of, for example, 0.001 fold mole or more, preferably 0.01 to 0.2 fold mole, and the phosphorus compound is preferably used in an amount of about 4 fold moles.
  • Cesium fluoride is preferably used in an amount of about 1 to 3 fold moles based on the tin compound of the formula (G).
  • the reaction temperature is, for example, 10°C or higher, preferably 60 to 100°C. As for these reactions, Gregory, C, Fu et al., Angew. Chem. Int. Ed., 2411 (1999 ) can be referred to.
  • the compounds of formula (D-a) can also be derived into compounds of the formula (D) by successively performing methods similar to those of Step 1-14, and Step 1-13.
  • the compounds of the formula (A) wherein Z a is -N(A 6 )(A 62 ), and A 62 is carbamimidoyl group can be prepared by, for example, guanidylation of a compound of the formula (A) wherein Z a is -NH(A 6 ) according to a known method (see, for example, Drake Brian, Patek Marcel, Lebl Michael, Synthesis, 6, 579 (1994) and the like) (Step 1-16).
  • the compounds of the formula (A) wherein Z a is -N(A 6 )(A 62 ), and A 62 is an alkylcarbonyl group, or an arylcarbonyl group can be prepared by, for example, reacting a compound of the formula (A) wherein Z a is -NH(A 6 ) with an acylation regent suitably corresponding to an target compound to be prepared in the same manner as that of Step 1-2-3 (Step 1-17).
  • the compounds represented by the formula (A-m) can be prepared from a compound represented by the following formula (H): [wherein R 1 , R 5 , R 6 , R 7 , R 8 , A 11 , and X 1 -X 2 have the same meanings as those defined above; and Y, A 1 , A 2 , and Z a have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded].
  • examples of the method include a method of allowing a reducing agent to react on a compound of the formula (H) in a solvent (Step 2-2-1).
  • the reducing agent include a metal hydride reducing agent such as sodium borohydride, zinc borohydride, borane/tetrahydrofuran complex, borane/pyridine complex, borane/triethylamine complex, borane/dimethyl sulfide complex, and lithium triethylboride, and preferred examples include sodium borohydride.
  • sodium borohydride is used in an amount of, for example, 0.5 fold mole or more, preferably 1 to 20 fold moles.
  • the solvent include alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran, 1,2- dimethoxy ethane, and 1,4-dioxane, dichloromethane, and N,N-dimethylformamide, and preferred examples include methanol, and ethanol.
  • the reaction temperature is, for example, 0°C or higher, preferably 10°C to the reflux temperature of the solvent.
  • the reaction time is, for example, 0.1 hour or more, preferably 0.5 to 12 hours.
  • the compounds of the formula (A-m) wherein Z a is -NH(A 6 ), -N(A 6 )(A 62 ), or -N(A 6 )(A 63 ) [wherein A 6 , A 62 , and A 63 have the same meanings as those defined above, provided that a compound wherein A 62 is carbamimidoyl group, an alkylcarbonyl group, or an arylcarbonyl group is excluded] can be prepared by reductively reacting a compound represented by the formula N(A 6 )H 2 , NH(A 6 )(A 62 ), or NH(A 6 )(A 63 ) with a compound of the formula (H) for amination (Step 2-2-2).
  • the reductive amination reaction can be performed by referring to a known method.
  • the method include, for example, a method of allowing a compound of the formula NH(A 6 )(A 61 ) mentioned above in an amount of 1 fold mole or more, preferably 1 to 10 fold moles, based on the compound of the formula (H), to react on the compound of the formula (H) in a 1,2-dichloroethane solvent in the presence of a reducing agent such as sodium triacetoxyborohydride in an amount of 0.5 fold mole or more, preferably 1 to 10 fold mole, based on the compound of the formula (H) at a temperature of 0°C or higher, preferably room temperature to 60°C.
  • a reducing agent such as sodium triacetoxyborohydride
  • a method of performing the reaction by using acetic acid as a solvent or in an amount of about 0.1 to 10 fold moles is also preferred. Further, preferred examples also include a method of performing the reaction in the presence of a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, and molecular sieves.
  • a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, and molecular sieves.
  • the compounds by directly reacting a compound of N(A 6 )(A 62 ) wherein A 62 is an alkyl group of which end is substituted with N(A 7 )(-X 3 -A 71 ) in the reductive amination of the compound of the formula (H) and NH(A 6 )(A 62 ).
  • the compounds of the formula (A-m) wherein Z a is -N(A 6 )(A 62 ), and A 62 is an alkyl group of which end is substituted with an alkylaminocarbonyloxy group, an alkyl group substituted with a cycloalkylaminocarbonyloxy group, or an alkyl group substituted with an arylaminocarbonyloxy group can be prepared in the same manner as that of Step 2-2-2 mentioned above by reductively reacting a compound of the formula (H) with NH(A 6 )(A 62 ) wherein A 62 is an alkyl group substituted with hydroxyl group for amination (Step 2-2-9), subsequently converting the aminated compound into an active ester in the same manner as that of Step 1-2-9 mentioned above, and then reacting the active ester with an alkylamine, cycloalkylamine, or arylamine suitably corresponding to an target compound to be prepared (Step 2-2-10).
  • a 62 is an alkyl group of which end is substituted with an alkylaminocarbonyloxy group, an alkyl group substituted with a cycloalkylaminocarbonyloxy group, or an alkyl group substituted with an arylaminocarbonyloxy group in the reductive amination of the compound of the formula (H) mentioned above.
  • the compounds of the formula (A-m) wherein Z a is -N(A 6 )(A 62 ), and A 62 is carbamimidoyl group can be prepared from a compound of the formula (A-m) wherein Z a is -NH(A 6 ) in the same manner as that of Step 1-16 (Step 2-3).
  • the compounds of the formula (A-m) wherein Z a is -N(A 6 )(A 62 ), and A 62 is an alkylcarbonyl group, or an arylcarbonyl group can be prepared from a compound of the formula (A-m) wherein Z a is -NH(A 6 ) in the same manner as that of Step 1-2-3 (Step 2-4).
  • the compounds represented by the following formula (1-b): [wherein R 1 , R 5 , R 6 , R 7 , R 8 , X 1 X 2 , All, and Z have the same meanings as those defined above; and Y, A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded] can be prepared from a compound of the formula (1-a). Specifically, the compounds of the formula (1-b) can be prepared by dehydrogenating a compound of the formula (1-a) in the same manner as that of Step 1-1-1 (Step 2-5).
  • the compounds of the formula (H) can be prepared form a compound represented by the following formula (J): [wherein n represents 2 or 3; R 1 , R 5 , R 6 , R 7 , R 8 , A 11 , and X 1 -X 2 have the same meanings as those defined above; and Y, A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded] (Step 2-6).
  • This step is a method of performing the reaction in a solvent in the presence of an acid catalyst.
  • the solvent include alcohols such as methanol, ethanol, tert-butanol, and ethylene glycol, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, nitromethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methylpyrolidone, sulfolane, acetic acid, and water, and methanol, ethanol, tert-butanol, tetrahydrofuran, and 1,4-dioxane are preferred.
  • Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, perchloric acid and the like, and hydrochloric acid, and perchloric acid are preferred.
  • the reaction temperature is, for example, 0°C or higher, preferably 10 to 120°C.
  • the reaction time is, for example, 0.1 hour or more, preferably 0.5 to 12 hours.
  • the compounds of the formula (J) mentioned above can be classified depending on the types of R 1 , R 5 , R 6 , R 7 , and R 8 into the following two types of compounds, Specifically, i) compounds represented by the following formula (J-a): [wherein n, A 11 , R 6 , R 7 , and R 8 have the same meanings as those defined above; and Y, A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded], which correspond to the compounds of the formula (J) wherein R 1 , and R 5 are hydrogen atoms, and ii) compounds represented by the following formula (J-b): [wherein n, A 11 , R 1 , and R 5 have
  • the compounds of the formula (J-a) can be prepared as follows. Specifically, the compounds can be prepared from a compound represented by the following formula (J-c): [wherein n, A 11 , and X 1 -X 2 have the same meanings as those defined above; and Y, A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded], which correspond to the compounds of the formula (J) wherein R 1 , R 5 , R 6 , R 7 , and R 8 are hydrogen atoms, by a combination of Steps 1-3, 1-4, 1-5, 1-6 of Preparation method 1, the aforementioned "coupling method using catalyst” and the like.
  • the compounds of the formula (J-b) mentioned above can be prepared as follows. Specifically, the compounds can be prepared from a compound of the following formula (J-d): [wherein R 11 , and R 51 independently represent hydrogen atom, or a halogen atom, n, A 11 , and X 1 -X 2 have the same meanings as those defined above; and Y, A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded], which correspond to the compounds of the formula (J) wherein R 1 , and R 5 independently represent hydrogen atom, or a halogen atom, and R 6 , R 7 , and R 8 are hydrogen atoms, according to Step 1-8 of Preparation method 1, or
  • the compounds of the formula (J-d) can be prepared by cyclizing a compound represented by the following formula (K) : [wherein n, R 11 , R 51 , A 11 , and X 1 -X 2 have the same meanings as those defined above; and Y, A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded] in the same manner as that of Step 1-9 mentioned above (Step 2-7).
  • the compounds of formula (L) can be prepared by performing reductive amination using a compound represented by the formula (D), and a compound represented by the following formula (N): [wherein n, and A 11 have the same meanings as those defined above; and Y a , A 1 , and A 2 have the same meanings as those defined above, provided that when any of combinations of A 6 and A 3 , A 6 and A 4 , A 6 and A 1 , A 6 and A 2 , A 2 and A 3 , A 2 and A 4 , A 6 and A 5 , A 3 and A 1 , and A 5 and A 1 is not present, said combination is excluded], which is commercially available, or can be prepared, instead of the compound of the formula (E), in the same manner as that of Step 1-11 (Step 2-9).
  • Examples of the method for the cyclization include a method of allowing a base to react on the compound in an inert solvent.
  • the inert solvent include ether type solvents such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane, benzene, toluene, dimethyl sulfoxide, N,N-dimethylformamide, 1-methylpyrolidone, and sulfolane, and tetrahydrofuran, and 1,4-dioxane are preferred.
  • the base examples include alkali metals such as sodium and potassium, alkali metal hydrides such as sodium hydride, and potassium hydride, alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, and potassium tert-butoxide, organic metal bases such as methyl lithium, n-butyl lithium, phenyl lithium, tert-butyl lithium, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium 2,2,6,6-tetramethylpiperizide and the like, potassium, potassium hydride, potassium tert-butoxide, and potassium bis(trimethylsilyl)amide are preferred, and potassium tert-butoxide is particularly preferred.
  • alkali metals such as sodium and potassium
  • alkali metal hydrides such as sodium hydride, and potassium hydride
  • the amount of the base used is, for example, 0.01 fold mole or more, preferably 0.1 to 5 fold moles, based on the compound of the formula (C-a).
  • the reaction temperature is, for example, 0°C or higher, preferably 10 to 120°C.
  • the reaction time is, for example, 0.001 hour or more, preferably 0.01 to 5 hours.
  • the compounds represented by the formula (C-a) constitute a part of the compounds represented by the formula (C) mentioned above, and the method for the preparation from 4-bromo-5-nitroisoquinoline is the same as that described above (Step 1-15), provided that a tin compound the following formula (G-a): [wherein R 2 , and Bu have the same meanings as those defined above], which constitutes a part of the tin compounds represented by the formula (G), can be used in the preparation of the compounds of the formula (F-a), or (F-b) from 4-bromo-5-nitroisoquinoline.
  • the compounds of the formula (A-k-1) constitute a part of the compounds of the formula (A-k) as described above, and therefore they can be derived into the compounds of the formula (1) wherein X 1 ⁇ X 2 is -CH(R 2 )-CH 2 - by such preparation steps starting from a compound of the formula (A-k) as described in Preparation method 1.
  • the compounds of the formula (L-a) constitute a part of the compounds of the formula (L) mentioned above, and the preparation method thereof is the same as that described above.
  • the compounds of the formula (J-d-1) constitute a part of the compounds of the formula (J-d) as described above, and therefore they can be derived into the compounds of the formula (1) wherein X 1 ⁇ X 2 is -CH(R 2 )-CH 2 - by such preparation steps starting from a compound of the formula (J-d) as described in Preparation method 2.
  • the compounds of the present invention represented by the aforementioned formula (1) and physiologically acceptable salts thereof have cell movement inhibitory actions on the basis of inhibition against phosphorylation of the myosin regulatory light chain in the cells, and are preferred as active ingredients of medicaments.
  • the cell contraction inhibitory action can be confirmed by measuring vasoconstriction inhibitory activity, tracheal relaxation activity, intraocular pressure reducing activity, respiratory tract constriction inhibitory activity, or the like.
  • the action to regulate change of cell morphology can be confirmed by, for example, measuring neurite outgrowth of nerve cells, or the like.
  • the inhibitory action on cell migration can be confirmed by measuring neutrophil migration inhibitory activity, respiratory tract inflammation suppressing activity, or the like.
  • the cell release inhibitory action can be confirmed by measuring the chemical mediator releasing amount from neutrophils.
  • the cell aggregation inhibitory action can be confirmed by measuring platelet aggregation inhibitory activity, or the like.
  • the apoptosis inhibitory action can be confirmed by, for example, giving stimulation to induce apoptosis to cells and then measuring cell viability or occurring frequencies of morphological changes of cells characteristic to apoptosis such as nuclear condensation, nuclear fragmentation, and blebbing of cells.
  • the cell movement inhibitory actions on the basis of the inhibition of phosphorylation of the myosin regulatory light chain in the cells are known to be associated with various biological actions as described in the section of related art in the specification, the cell movement inhibitory actions must be construed in their broadest sense including the aforementioned cell contraction inhibitory action, action to regulate change of cell morphology, cell migration inhibitory action, cell release inhibitory action, cell aggregation inhibitory action, and apoptosis inhibitory action.
  • the compounds of the present invention represented by the aforementioned formula (1) and salts thereof have an inhibitory activity against phosphorylation of the myosin regulatory light chain (see, Test Example 1 of the specification), vasoconstriction inhibitory activity (see, Test Example 2 in the specification), antigen stimulation-induced respiratory tract constriction suppressing activity (see, Test Example 3 in the specification), intraocular pressure reducing activity (see, Test Example 4 in the specification), neurite outgrowth activity (see, Test Example 5 in the specification), neutrophil migration inhibitory activity (see, Test Example 6 in the specification), chronic respiratory tract inflammation suppressing activity (see, Test Example 7 in the specification), acute respiratory tract inflammation inhibitory activity (see, Test Example 8 in the specification), tracheal relaxation activity (see, Test Example 11 in the specification), and constriction elicitor-induced respiratory tract constriction suppressing activity (see, Test Example 12 in the specification).
  • the compounds represented by the aforementioned formula (1) and salts thereof have notably higher vasoconstriction inhibitory activity, antigen stimulation-induced respiratory tract constriction inhibitory activity, intraocular pressure reducing activity, neurite outgrowth activity, neutrophil migration inhibitory activity, chronic respiratory tract inflammation suppressing activity, acute respiratory tract inflammation inhibitory activity, tracheal relaxation activity, and constriction elicitor-induced respiratory tract constriction suppressing activity as compared with the conventional isoquinoline compounds.
  • the compounds represented by the aforementioned formula (1) and salts thereof are useful as active ingredients of medicaments for prophylactic and/or therapeutic treatment of diseases relating to contraction of various cells, diseases relating to morphological change of various cells, diseases relating to migration of various cells, diseases relating to release of various cells, diseases relating to aggregation of various cells, and/or diseases relating to apoptosis of various cells and the like.
  • action mechanism of the compounds of the present invention represented by the aforementioned general formula (1) and salts thereof can be presumed as follows. It is known that increase of the amount of phosphorylated myosin regulatory light chain activates the actomyosin system, which is a movement apparatus of cytoskeleton, and activates cell movements. Therefore, it is considered that the phosphorylation reaction of myosin regulatory light chain is important for cell movements ( Kamm, K., et al., Annu. Rev.
  • Rho kinase The activity of Rho kinase can be measured by the method disclosed in WO01/56988 . More specifically, ATP ( ⁇ 32 P-ATP) is added to a substrate (Ribosomal S6 kinase substrate) together with a commercially available Rho kinase (Upstate) to start the enzymatic reaction and phosphorylate the substrate. The substrate is adsorbed on filter paper, and ATP is washed off with the phosphate buffer. Then, the amount of the phosphorylated substrate is measured by using a liquid scintillation counter.
  • ATP ⁇ 32 P-ATP
  • the inhibitory activity of the compounds of the present invention represented by the aforementioned formula (1) for the Rho kinase activity can be determined by adding the compounds before starting the enzymatic reaction, and measuring suppression of the phosphorylation amount of the substrate.
  • the phosphorylation reaction of myosin phosphatase can be measured by, for example, using an antibody specifically recognizing the phosphorylated myosin phosphatase ( Feng, J. et al., J. Biol. Chem., 274, pp.37385-37390, 1999 ). More specifically, proteins including myosin phosphatase are extracted from a tissue, subjected to electrophoresis on acrylamide gel, and transferred to a nitrocellulose membrane.
  • the proteins are reacted with antibodies specifically recognizing phosphorylated myosin phosphatase to detect the amount of phosphorylated myosin phosphatase.
  • the inhibitory activity on the phosphorylation reaction of myosin phosphatase can be determined by adding the compounds before starting the extraction from the tissue, and measuring suppression of the phosphorylation amount of the myosin phosphatase.
  • the compounds of the present invention represented by the aforementioned formula (1) and salts thereof inhibit the Rho/Rho kinase pathway, which is Reaction route 2 mentioned above, and exhibit more potent cell contraction inhibitory activity and cell migration inhibitory activity compared with the conventional isoquinoline compounds. It is known that the Rho/Rho kinase route plays an important role for cell contraction and cell migration.
  • Rho/Rho kinase pathway controls a variety of cellular functions such as aggregation, release, production, division, apoptosis, and gene expression in various cell lines ( Fukata, Y., et al., Trends in Pharmacological Sciences, 22, pp.32-39, 2001 ; Murata T., et al., J. Hepatotol., 35, pp.474-481, 2001 ; Ohnaka, K., et al., Biochem. Biophys. Res. Commun., 287, pp.337-342, 2001 ; Yuhong, S., et al., Exp.
  • the compounds of the present invention which inhibit the Rho/Rho kinase pathway exhibit, based on that effect, more potent cell contraction inhibitory activity (Test Examples 2, 3, 4, 11, and 12), cell morphology change regulating activity (Test Example 5), cell migration inhibitory activity (Test Examples 6, 7, and 8), cell release inhibitory activity, cell aggregation inhibitory activity, apoptosis inhibitory activity, and activity of regulating gene expression compared with the conventional isoquinoline compounds, and are useful as active ingredients of medicaments for prophylactic and/or therapeutic treatment of diseases relating to contraction of various cells, diseases relating to morphological change of various cells, diseases relating to migration of various cells, diseases relating to release from various cells, diseases relating to aggregation of various cells, diseases relating to apoptosis of various cells, and/or diseases relating to abnormal gene expression in various cells ( Jikken Igaku (Experimental Medicine) Vol. 17, 7, 1999 ).
  • Examples of the diseases relating to contraction of various cells include, for example, as those relating to vascular smooth muscles, hypertension, arteriosclerosis, cerebral circulatory disturbance, brain function disorder with the aforementioned disease (mental disorder, memory disorder, dementia, delirium, poriomania, dyskinesia and the like), dizziness, auditory disturbance, cardiac diseases, pokkuri-byou (sudden death), disturbances of peripheral circulation, disturbances of retinal circulation, renal failure and the like, as those relating to airway smooth muscles, asthma, acute respiratory distress syndrome (ARDS), pulmonary emphysema, peripheral respiratory tract disease, chronic bronchitis, chronic obstructive pulmonary disease (COPD) and the like ( Ueki, J.
  • ARDS acute respiratory distress syndrome
  • COPD chronic obstructive pulmonary disease
  • hypertension examples include essential hypertension, renal hypertension, renovascular hypertension, hypertension during pregnancy, endocrine hypertension, cardiovascular hypertension, neurogenic hypertension, iatrogenic hypertension, pulmonary hypertension and the like
  • arteriosclerosis examples include those in which pathological change is observed in major arteries in whole body such as coronary artery, aorta abdominalis, renal artery, carotid artery, ophthalmic artery, and cerebral artery.
  • cerebral circulatory disturbance examples include cerebral thrombosis, cerebral infarction, cerebral hemorrhage, transient brain ischemic attack, hypertensive encephalopathy, cerebral arteriosclerosis, subdural hemorrhage, epidural hemorrhage, subarachnoid hemorrhage, brain hypoxia, cerebral edema, encephalitis, brain tumor, head injury, mental disorder, metabolic intoxication, drug intoxication, transient asphyxia, deep anesthesia in operation and the like.
  • the cardiac diseases include congestive heart failure, acute myocardial infarction, previous myocardial infarction, subendocardial infarction, right ventricular infarction, atypical myocardial infarction, ischemic cardiomyopathy, variant angina pectoris, stable angina, effort angina, coronary vasospasm, postinfarction angina, unstable angina pectoris, arrhythmia, and acute cardiac death.
  • the peripheral circulatory disturbances include aortic diseases such as Buerger's disease, arteriosclerotic obliteration, and Raynaud's syndrome, venous diseases such as venous thrombosis and thrombophlebitis, hyperviscosity syndrome, frostbite and chilblain, psychoesthesia and hypnagogic disturbance due to feeling of cold, bedsore, cleft, and alopecia.
  • aortic diseases such as Buerger's disease, arteriosclerotic obliteration, and Raynaud's syndrome
  • venous diseases such as venous thrombosis and thrombophlebitis
  • hyperviscosity syndrome such as venous thrombosis and thrombophlebitis
  • frostbite and chilblain venous thrombosis and thrombophlebitis
  • hyperviscosity syndrome such as venous thrombosis and thromboph
  • Glaucoma includes primary glaucoma, secondary glaucoma, developmental glaucoma, childhood secondary glaucoma and the like, as well as more narrowly classified types of the foregoings, including primary open-angle glaucoma, primary angle-closure glaucoma, mixed-type glaucoma, ocular hypertension and the like ( Japanese Journal of Ophthalmology, vol. 107, No. 3, 2003 ).
  • vitreoretinal diseases include retinal detachment, retinoschisis, vitreoretinal interface syndrome, retinal pigment epitheliosis, macular hole, phacomatosis, vitreous hemorrhage, retinal circulatory disturbances and the like
  • the vitreoretinal diseases mentioned herein include more narrowly classified diseases belonging to each of the categories according to the pathological typology described in Shin Zusetsu Rinsho Ganka Koza (Illustrative Lecture of Clinical Ophthalmology, New Edition), Ed. By Tano, Y., Araie, M., et al, Vol. 5, Vitreoretinal Diseases, MEDICAL VIEW, 2003 ).
  • the urinary disturbances include dysuria, bladder neck contracture, bladder neck occlusion, urethral syndrome, detrusor sphincter dyssynergia, unstable bladder, chronic prostatitis, chronic cystitis, prostate pain, Hinman's syndrome, Fowler's syndrome, psychogenic dysuria, drug-induced dysuria, dysuria with aging and the like.
  • the erectile dysfunction include organic erectile dysfunction accompanying diseases of diabetes mellitus, arteriosclerosis, hypertension, multiple-sclerotic cardiac diseases, hyperlipidemia, depression and the like, functional erectile dysfunction, erectile dysfunction with aging, and erectile dysfunction after spinal cord injury or radical prostatectomy.
  • Examples of the diseases relating to morphological change of various cells include, for example, various nerve dysfunctions as those relating to nerve cells.
  • nerve dysfunctions for example, neural damages caused by trauma (spinal cord injury and the like), neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, diabetic retinopathy, and glaucoma and the like can be exemplified.
  • Glaucoma refers to the same as that mentioned above.
  • Examples of the diseases relating to migration of various cells include, for example, as those relating to cancer cells, infiltration and metastasis of cancer.
  • Examples of those relating to vascular endothelial cells include angiogenesis, neovascular maculopathy, macular edema and the like (the macular diseases mentioned herein include more narrowly classified diseases belonging to each of the categories according to the pathological typology described in Shin Zusetsu Rinsho Ganka Koza (Illustrative Lecture of Clinical Ophthalmology, New Edition), Ed. By Tano, Y., Araie, M., et al, Vol. 5, Vitreoretinal Diseases, MEDICAL VIEW, 2003 ).
  • Examples of those relating to leukocytes include bacterial infection, allergic hypersensitive diseases (e.g., bronchial asthma, atopic dermatitis, pollinosis, anaphylactic shock and the like), collagen diseases (e.g., rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis, Sjogren's disease and the like), angiitis, inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's disease and the like), ischemic reperfusion injury of visceral organs, traumatic spinal cord injury, pneumonia, hepatitis, nephritis, pancreatitis, otitis media, sinusitis, arthritis (for example, osteoarthritis, gout and the like can be exemplified), fibrosis, AIDS, adult T-cell leukemia, rejection after organ transplantation (graft versus host reaction), vascular restenosis, and endotoxin shock.
  • Example of the cancer include myelocytic leukemia, lymphatic leukemia, gastric cancer, carcinoma of the colon and rectum, lung cancer, pancreatic carcinoma, hepatocellular carcinoma, carcinoma of the esophagus, ovarian cancer, breast cancer, skin cancer, head and neck cancer, cancer of the testicles, neuroblastoma, urinary tract epithelial cancer, multiple myeloma, carcinoma uteri, melanoma, brain tumor and the like.
  • hepatitis include hepatitis by virus infection (e.g., hepatitis B, hepatitis C and the like), and alcoholic hepatitis.
  • Examples of the pneumonia include chronic obstructive pulmonary disease (COPD) and interstitial pneumonia, which may shift to fibrosis.
  • COPD chronic obstructive pulmonary disease
  • Examples of nephritis include chronic nephritic syndrome, asymptomatic proteinuria, acute nephritic syndrome, nephrotic syndrome, IgA nephropathy, pyelonephritis, glomerulonephritis and the like.
  • Fibrosis include chronic pathological changes characterized by excess deposition of connective tissue proteins in lung, skin, heart, liver, pancreas, kidney and the like. The major pathological conditions are pulmonary fibrosis, hepatic fibrosis, and skin fibrosis. However, fibrosis is not limited to these examples.
  • hepatic fibrosis In hepatic fibrosis, viral hepatitis progresses by infection of, in particular, hepatitis B virus or hepatitis C virus, thus hepatic cells cause necrosis, and thereby fibrosis progresses, which means macronodular hepatic cirrhosis. Further, hepatic fibrosis also includes micronodular hepatic cirrhosis caused by progress of alcoholic hepatitis.
  • Examples of diseases relating to release of various cells include, as those relating to leukocytes, for example, allergic diseases.
  • allergic diseases include asthma, atopic dermatitis, allergic conjunctivitis, allergic arthritis, allergic rhinitis, allergic pharyngitis and the like.
  • diseases relating to aggregation of various cells include, as those relating to platelets, for example, thrombosis.
  • Thrombosis include the aforementioned circulatory disturbances of major arteries, major veins and peripheral arteries and veins in whole body, as well as shock caused by hemorrhage, drug intoxication, or endotoxin, disseminated intravascular coagulation (DIC) following it, and multiple organ failure (MOF).
  • Examples of the diseases relating to apoptosis of various cells include, as those relating to nerves, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, diabetic peripheral neuropathy, retinopathy, amyotrophic lateral sclerosis due to cerebral ischemia, pigmented retinitis, and cerebellar degeneration, and glaucoma. Examples of glaucoma are mentioned above.
  • AIDS, and fulminant hepatitis are examples of disease relating to viruses
  • chronic heart failure due to myocardial ischemia is an example of diseases relating to smooth muscles
  • myelodysplasia is an example of diseases relating to smooth muscles
  • myelodysplasia is an example of diseases relating to smooth muscles
  • myelodysplasia is an example of diseases relating to smooth muscles
  • myelodysplasia aplastic anemia
  • sideroblastic anemia graft-versus-host disease (GVHD) after organ transplantation
  • GVHD graft-versus-host disease
  • diseases relating to blood arthrosteitis
  • osteoporosis is an example of diseases relating to bones.
  • Examples of the diseases relating to abnormal gene expression of various cells include, for example, bone diseases as those relating to bone cells, AIDS as one relating to virus, cancers as those relating to cancer cells, and neurogenic pain (also called neuropathic pain) as one relating to nerve cells.
  • Examples of the bone diseases include osteoporosis, hypercalcemia, bone Paget's disease, renal osteodystrophy, rheumatoid arthritis, osteoarthritis, osteogenesis imperfecta tarda, bone damage, periodontal bone disorder and the like.
  • Examples of AIDS include acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) infection.
  • Examples of the cancers include gastric cancer, carcinoma of the colon and rectum, hepatocellular carcinoma, pancreatic carcinoma, lung cancer, leukemia, malignant lymphoma, carcinoma uteri, ovarian cancer, breast cancer, skin cancer and the like.
  • Neurogenic pain include peripheral neurogenic pain and central neurogenic pain.
  • peripheral neurogenic pain include, for example, traumatic nerve injury, ischemic neuropathy, multiple neurosis, nerve-plexus injury, compression of nerve root, stump pain after dismemberment, postherpetic neuralgia, trigeminal neuralgia and the like
  • examples of central neurogenic pain include, for example, cerebral apoplexy, multiple sclerosis, spinal cord injury, epilepsy and the like ( Yuge T. et al., Medical Care Practice of Anesthesiology 6, Current Situation of Neuropathic Pain, Bunko-do, 2002 ).
  • the usefulness as a medicament for hypertension can be confirmed based on an action of reducing the diastolic blood pressure.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of pulmonary hypertension can be confirmed by using, for example, a rat model of pulmonary hypertension created by administering monocrotaline to a rat for 2 to 3 weeks ( Ito, K.M. et al., Am. J. Physiol., 279, H1786-H1795, 2000 ).
  • a compound is orally, intravenously or intraperitoneally administered to a model animal of pulmonary hypertension at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and the intrapulmonary pressure is measured.
  • the usefulness as a medicament for pulmonary hypertension can be confirmed based on an action of decreasing the intrapulmonary pressure.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of arteriosclerosis can be confirmed by using, for example, a rat model of L-NAME-induced arteriosclerosis ( Cir. Res. 89(5):415-21, 2001 ), a rat model of balloon-induced neointimal formation ( Sawada N.
  • a compound is orally, intravenously or intraperitoneally administered to a model animal of arteriosclerosis at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and thickening of arteries is observed.
  • the usefulness as a medicament for arteriosclerosis can be confirmed based on an action of suppressing neointimal formation in arteries.
  • a compound is orally, intravenously or intraperitoneally administered to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and the amount of energy-related substances and survival period of gerbil, or inhibition of late-onset of neuronal death is measured.
  • the usefulness as a medicament for cerebral circulatory dysfunction can be confirmed based on actions for maintaining, improving and activating cerebral metabolic ability, brain and nerve protective action, and action for suppressing formation of cerebral infarction.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of cardiac diseases can be confirmed by using, for example, a rat model of myocardial infarction based on the ligation of artery ( Xia Q.G. et al., Cardiovasc. Res., 49(1):110-7, 2001 ) or the like.
  • Effectiveness as a medicament for cardiac diseases can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and observing a cardiac tissue fixed by formalin perfusion after ischemic reperfusion.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of disturbances of peripheral circulation can be confirmed by using, for example, a rat model of bedsore ( Pierce S.M. et al., Am. J. Physiol. Heart Circ. Physiol., 281(1):H67-74, 2001 ) or the like.
  • Effectiveness as a medicament for bedsore can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, compressing the hind leg skin at a pressure of 50 mmHg, and then observing a tissue of necrotic area of the lesion or measuring epithelial blood flow of the same.
  • Effectiveness as a medicament for retinal circulatory disturbance can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and comparing the degree of retinal circulatory disturbance with that of a control based on count of laser spots to evaluate degree of the action and sustainment of the action.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of renal failure can be confirmed by using, for example, a rat model of one-kidney, one-clip renal hypertension ( Kiso to Rinsho, 30, 511-524, 1996 ).
  • Effectiveness as a medicament for renal failure can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the diuretic effect.
  • constriction elicitor-induced respiratory tract constriction model histamine, acetylcholine and the like are generally used, Daniela, S. et al., J. Pharmacol. Exp. Ther., 297(1), pp.280-290, 2001
  • LPS-induced acute respiratory tract inflammation model inhibition of human peripheral blood leucocyte migration and the like.
  • the usefulness as a medicament for bronchial asthma can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring elevation of airway resistance caused by tracheal constriction or relaxation, antigen stimulation, histamine inhalation, or acetylcholine inhalation, migrating leucocyte count in bronchoalveolar lavage fluid and the like, or performing histological analysis.
  • the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of irritable bowel syndrome can be confirmed by administering the compounds to a stress burden model animal, or the like.
  • the stress burden model animal include, for example, a rat model of arresting stress ( Miyata, K. et al., J. Pharmacol. Exp. Ther., 259, pp.815-819, 1991 ), a CRH-administered rat model ( Miyata, K. et al., Am. J. Physiol., 274, G827-831, 1998 ) and the like.
  • a compound is orally, intravenously or intraperitoneally administered to a stress burden model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and counting the number of fecal pellets.
  • the usefulness as a medicament for curative medicine of irritable bowel syndrome can be confirmed based on effect for reducing the number of fecal pellets.
  • the usefulness as a medicament for glaucoma can be confirmed by instilling or orally, intravenously or intraperitoneally administering a compound to a locally anesthetized rat or monkey model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the intraocular pressure over time using an tonometer to evaluate degree of the intraocular pressure reducing activity, or sustainment of the intraocular pressure reducing activity.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of vitreoretinal diseases can be confirmed by a known method, for example, the methods described in Oshima, Y.
  • the usefulness as a medicament for vitreoretinal diseases can be confirmed by orally, intravenously, intraperitoneally, or intraocularly administering (direct administration to vitreum or retina) a compound to a rabbit in which retinal detachment is induced by cell transfer to the vitreoretinal interface, vitrectomy, or the like at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and evaluating amelioration of the pathological conditions on the basis of histological analysis.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of dysuria can be confirmed by using, for example, a model of rhythmic bladder contraction ( Kaneko S.
  • the usefulness as a medicament for urinary disturbance can be confirmed by orally, intravenously or intraperitoneally administering a compound to an anesthetized rat or dog at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the number of rhythmic contraction of filled bladder (micturition).
  • the number of erection of the penis per 30 minutes can be counted to confirm the usefulness as a medicament for erectile dysfunction.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for suppressing cancer metastasis and invasion can be confirmed by, for example, the method described in Cancer Res., 55:3551-3557 (1995) .
  • the usefulness as a medicament for cancer metastasis and invasion can be confirmed by orally, intravenously or intraperitoneally administering a compound at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, to a nude mouse transplanted with human cancer cell suspension transplantable to immunodeficient mice at the same site (spontaneous metastasis model), and measuring the metastasized lesion.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of collagen disease can be confirmed by using, for example, collagen-induced arthritis model of a rat or mouse ( Griffith, M.M.
  • the usefulness as a medicament for collagen disease can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model mouse or rat at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring footpad volume or progression of bone destruction.
  • the usefulness as a medicament for inflammatory bowel disease can be confirmed by, for example, orally, intravenously or intraperitoneally administering a compound at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, to a rat in which colitis is induced by intraintestinal injection of acetic acid, dissecting the rat after several days to two weeks, then observing and measuring the ulcer area of the intestinal epithelium, and amount of leucotriene B4 in a colon homogenate.
  • Effectiveness as a medicament for pneumonia can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and evaluating change in number of eosinophils or monocytes in the pulmonary cavity, and histological findings of inflammation.
  • the usefulness as a medicament for hepatitis can be confirmed by orally, intravenously or intraperitoneally administering a compound to the mouse model of endotoxin-induced liver injury at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the plasmic transaminase level or amount of hydroxyproline in a hepatic tissue, which are indicators of liver function, or performing histological analysis.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of pancreatitis can be confirmed by using, for example, a mouse model of cerulein inducted acute pancreatitis ( Niedirau, C.
  • Effectiveness as a medicament for pancreatitis can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the serum amylase activity, or weight of pancreas.
  • nephritis rat model prepared by administering anti-GBM antibodies obtained by immunizing a rabbit with a GBM fraction derived from a rat to a rat ( WO01/56988 ), or the like.
  • a compound is orally, intravenously or intraperitoneally administered to the nephritis rat model at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and the urinary proteins are measured.
  • the usefulness as a medicament for nephritis can be confirmed based on an action of reducing the urinary protein level.
  • the usefulness as a medicament for rheumatoid arthritis can be confirmed by orally, intravenously or intraperitoneally administering a compound to a model mouse or model rat at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring footpad volume or progression of bone destruction.
  • COPD chronic obstructive pulmonary disease
  • the usefulness as a medicament for COPD can be confirmed by orally, intravenously or intraperitoneally administering a compound to any of the model animals mentioned above at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring tracheal constriction or relaxation, change in airway resistance, migrating leucocyte count in bronchoalveolar lavage fluid, change in number of number of eosinophils or monocytes in the pulmonary cavity, or histological findings of inflammation.
  • the usefulness as a medicament for hepatic fibrosis can be confirmed by orally, intravenously or intraperitoneally administering a compound to the hepatic fibrosis model at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring the plasmic transaminase level, or amount of hydroxyproline in a hepatic tissue, which are indicators of liver function, or performing histological analysis.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of pulmonary fibrosis can be confirmed by using an animal model of Bleomycin-induced pulmonary fibrosis according to the method described in, for example, Am. J.
  • the usefulness as a medicament for pulmonary fibrosis can be confirmed by orally, intravenously or intraperitoneally administering a compound to the pulmonary fibrosis mouse model at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring respiratory function, or amount of hydroxyproline in a pulmonary tissue.
  • the usefulness as a medicament for allergy can be confirmed by orally, intravenously or intraperitoneally administering a compound to an NC/Nga mouse pretreated with a surfactant or an organic solvent at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, when eruption is induced in the mouse by using housedust mite antigens, and measuring the plasmic IgE level, number of eosinophils and the like.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of thrombosis can be confirmed by using, for example, a rabbit model of experimentally-induced venous thrombus ( Maekawa, T.
  • Effectiveness as a medicament for thrombosis can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and estimating the incidence of thrombus.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) as active ingredients of medicaments for prophylactic and/or therapeutic treatment of Alzheimer's disease can be confirmed by using, for example, an in vitro culture system of nerve cells derived from rat embryos ( Yankner, B.A.
  • Effectiveness as a medicament for Alzheimer's disease can be confirmed by adding 0.1 to 1 mM, preferably 0.1 to 100 ⁇ M, of a compound, and measuring suppression ratio for cell death induced by beta-amyloid proteins.
  • the usefulness as a medicament for periodontal bone disorder or osteoporosis can be confirmed based on an action for suppressing periodontal breakdowns, or an action for suppressing skeletal bone weight loss.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of AIDS can be confirmed by using, for example, a rhesus monkey model of SIV-infection ( Crub S. et al., Acta Neuropathol., 101(2), pp.85-91, 2001 ) or the like.
  • Effectiveness as a medicament for AIDS can be confirmed by orally, intravenously or intraperitoneally administering a compound to the model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and quantifying the SIV mRNA level in blood.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of cancer can be confirmed by using, for example, a mouse model of ultraviolet ray irradiation-induced skin cancer, a nude mouse model of tumor xenograft ( Orengo I.F. et al., Arch Dermatol., 138(6), pp.823-824, 2002 ; Ki D.W.
  • Effectiveness as a medicament for cancer can be confirmed by orally, intravenously or intraperitoneally administering a compound to a model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and observing progression or reduction of the grafted cancer tissues on the body surface.
  • Usefulness of the compounds of the present invention represented by the aforementioned formula (1) and salts thereof as active ingredients of medicaments for prophylactic and/or therapeutic treatment of neurogenic pain can be confirmed by using, for example, a spared nerve injury model ( Bennett, GJ. et al., Pain, 33(1) pp.87-107 (1988) ), or the lie.
  • Effectiveness as a medicament for neurogenic pain can be confirmed by orally, intravenously or intraperitoneally administering a compound to a model animal at a dose of 0.1 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and measuring change of response to pain caused by thermal or physical stimulation.
  • the compounds of the present invention represented by the formula (1) are useful as the medicaments mentioned above.
  • test compounds of the compounds of the present invention or salts thereof were introduced into wells of a 96-well plate at a concentration three times higher than the IC 50 values obtained in Test Example 1, and the cell suspension prepared in Test Example 1 was added at a density of 10 6 /well, incubated for 30 minutes at room temperature and stained with trypan blue to determine the survival rates of the cells, a viability as high as 90% or more was observed in all the wells. Furthermore, when the compounds of the present invention or salts thereof were orally administered to mice every day at a dose of 30 mg/kg for 5 days, death was not observed. Therefore, the compounds of the present invention had no particular problem also in safety.
  • a pharmaceutical composition containing one or more kinds of the aforementioned substances as the active ingredients and one or more kinds of pharmaceutical additives can be generally prepared and administrated orally or parenterally (e.g., intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, intrapulmonary administration, intranasal administration, instillation, intraurethral administration, intravaginal administration, sublingual administration, intrarectal administration and the like) to human or an animal other than human.
  • the aforementioned pharmaceutical composition can be prepared in a dosage form suitable for an intended administration route.
  • examples of the pharmaceutical composition suitable for oral administration include oral drug products (tablets, film-coated tablets, intraoral collapsing tablets, hard capsules, soft capsules, powders, fine granules, granules, dry syrups, syrups, pills, troches and the like), and examples of the pharmaceutical composition suitable for parenteral administration include injections (liquid dosage forms, lyophilized dosage forms, suspensions and the like), inhalants, suppositories, transdermally absorbed agents (e.g., tapes), ointments, ophthalmic solutions, ophthalmic ointments, ophthalmic membrane adherent agents and the like.
  • oral drug products tablets, film-coated tablets, intraoral collapsing tablets, hard capsules, soft capsules, powders, fine granules, granules, dry syrups, syrups, pills, troches and the like
  • examples of the pharmaceutical composition suitable for parenteral administration include injections (liquid dosage forms, lyophilized dosage
  • preferred examples of the dosage form include oral drug products, ophthalmic solutions, ophthalmic ointments, and ophthalmic membrane adherent agents.
  • preferred dosage forms for bronchial asthma or chronic obstructive pulmonary disease include oral drug products, inhalants (for example, a method of inhaling powder of the pharmaceutical composition or a liquid dosage form prepared by dissolving or suspending the pharmaceutical composition in a solvent as it is, or inhaling mist thereof by using a sprayer called atomizer or nebulizer), and transdermal preparations.
  • compositions can be prepared in a conventional manner by using pharmaceutical additives generally used in this field (e.g., excipients, disintegrants, binders, lubricants, colorants, buffering agents, coating agents, flavors, fragrances, emulsifying agents, isotonic agents, solubilizing agents, preservatives, viscosity improvers, pH adjusters and the like).
  • pharmaceutical additives generally used in this field (e.g., excipients, disintegrants, binders, lubricants, colorants, buffering agents, coating agents, flavors, fragrances, emulsifying agents, isotonic agents, solubilizing agents, preservatives, viscosity improvers, pH adjusters and the like).
  • excipients examples include saccharides such as lactose, sucrose, and trehalose, sugar alcohols such as D-mannitol, erythritol, xylitol, and sorbitol, starches such as maize starch, crystalline cellulose, calcium hydrogenphosphate and the like
  • examples of the disintegrants include starches, partially pregelatinized starch, carmellose and metal salts thereof, croscarmellose sodium, sodium carboxymethyl starch, agar powder, crospovidone, low substituted hydroxypropylcellulose and the like
  • examples of the binders include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methylcellulose, ethylcellulose, popidone, acacia powder, pullulan, pregelatinized starch and the like
  • examples of the lubricants include stearic acid and metal salts thereof, talc, silicic acid and metal salts thereof, salt-hardened oil, suc
  • compositions When solid pharmaceutical compositions are prepared, there are used pharmaceutical additives including, for example, sucrose, lactose, glucose, fructose, trehalose, D-mannitol, sorbitol, erythritol, xylitol, maltitol, maize starch, potato starch, wheat starch, rice starch, crystalline cellulose, carmellose, carmellose calcium, low substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, dextrin, cyclodextrin, dextran, agar, xanthane gum, guar gum, rosin, acacia, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, povidone, pregelatinized starch, partly pregelatinized starch, pullulan, pectin, polysorbate, polyethylene glycol, propylene glycol, glycerol, magnesium
  • compositions When semi-solid pharmaceutical compositions are prepared, there are used pharmaceutical additives including, for example, animal fats and oils (olive oil, maize oil, castor oil and the like), mineral fats and oils (vaseline, white petrolatum, solid paraffin and the like), waxes (jojoba oil, carnauba wax, beeswax and the like), partially or totally synthesized glycerol fatty acid esters.
  • animal fats and oils oil, maize oil, castor oil and the like
  • mineral fats and oils vaseline, white petrolatum, solid paraffin and the like
  • waxes jojoba oil, carnauba wax, beeswax and the like
  • partially or totally synthesized glycerol fatty acid esters examples include Witepsol (Dynamit Nobel), Pharmasol (Nippon Oil & Fats) and the like.
  • liquid pharmaceutical compositions When liquid pharmaceutical compositions are prepared, pharmaceutical additives including, for example, sodium chloride, glucose, sorbitol, glycerol, olive oil, propylene glycol, ethyl alcohol and the like can be used.
  • sterile liquid media for example, physiological saline, isotonic solutions, oily liquids such as sesame oil and soybean oil are used.
  • suitable suspending agents such as carboxymethylcellulose sodium, nonionic surfactants, solubilizing agents such as benzyl benzoate and benzyl alcohol and the like may be used together.
  • eye drops When eye drops are prepared, they can be prepared as aqueous liquids or aqueous solutions.
  • aqueous solutions can be prepared by using a sterile aqueous solution for injections.
  • various additives such as buffers (borate buffers, acetate buffers, carbonate buffers and the like are preferred in view of reduction of stimulus), isotonic agents (for example, sodium chloride, potassium chloride and the like can be mentioned), preservatives (for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzyl alcohol, chlorobutanol and the like can be mentioned), viscosity improvers (for example, methylcellulose, sodium carboxymethylcellulose and the like can be mentioned) and the like may be optionally added.
  • buffers borate buffers, acetate buffers, carbonate buffers and the like are preferred in view of reduction of stimulus
  • isotonic agents for example, sodium chloride, potassium chloride and the like can be mentioned
  • preservatives for example, methyl paraoxybenzoate, ethyl paraoxybenzoate, benzyl alcohol, chlor
  • preparation of inhalants when the composition is inhaled as powder, for example, preparation of the aforementioned solid pharmaceutical composition can be referred to, and the obtained powder is preferably further pulverized.
  • preferable methods include a method of preparing the pharmaceutical composition by referring to the aforementioned preparation of solid pharmaceutical composition to prepare a solid composition and dissolving the solid in distilled water or a suitable solvent to obtain a medicament solution upon use, or a method of preparing the pharmaceutical composition by referring to the aforementioned preparation of liquid pharmaceutical composition to obtain a medicament solution.
  • the size of particles in the aforementioned powder or medicament solution is preferably a particle size suitable for inhalation, and the upper limit of the size is, for example, preferably 100 ⁇ m or less, more preferably 50 ⁇ m or less, particularly preferably 10 ⁇ m or less.
  • the lower limit of the particle size is not particularly limited, and a smaller particle size is more preferred.
  • a content of the active ingredient in the aforementioned pharmaceutical composition can be suitably chosen depending on a dosage form.
  • the limit is preferably 0.0001% by weight or more, 0.001% by weight or more, 0.01% by weight or more, 0.1% by weight or more, or 1% by weight or more, based on the total weight of the composition.
  • the upper limit of the content of the active ingredient is not also particularly limited so long as the effect of the present invention is exhibited, the limit is preferably 100% by weight or less, 80% by weight or less, 50% by weight or less, 10% by weight or less, 5% by weight or less, 1% by weight or less, or 0.1% by weight or less.
  • a dose of the medicament of the present invention can be suitably determined for each administration in consideration of the age, weight, sexuality of a patient, the type of a disease, the severity of pathological condition and the like.
  • the lower limit is, for example, preferably 0.01 mg or more, 0.1 mg or more, or 1 mg or more.
  • the upper limit is, for example, preferably 1000 mg or less, 500 mg or less, 100 mg or less, or 30 mg or less.
  • a drug used for the combination with the compound (i) or (ii) is hereinafter referred to as a jointly-used drug.
  • a jointly-used drug for example, drugs in various molecular forms such as low molecular weight compounds, low molecular peptides, polypeptides, nucleic acid oligomers, peptide-nucleic acid (PNA) oligomers, and antibodies can be used, and the drug can be chosen depending on administration object, administration route, objective disease and the like from various drugs of which objective diseases are diseases relating to contraction of various cells, diseases relating to morphological change of various cells, diseases relating to migration of various cells, diseases relating to release from various cells, diseases relating to aggregation of various cells, diseases relating to apoptosis of various cells, diseases relating to abnormal gene expression in various cells and the like (provided that (i) and (ii) are excluded).
  • a medicament characterized by comprising (i) and a jointly-used drug in combination may sometimes be more preferred compared with a pharmaceutical composition comprising (i) solely as an active ingredient.
  • Such characteristic feature can be understood by any kind of more preferred result provided by a medicament comprising (i) and a jointly-used drug in combination compared with a pharmaceutical composition comprising solely (i) in any test method described below.
  • explanations for a medicament comprising (i) and a jointly-used drug is also applied to a medicament comprising (ii) and a jointly-used drug, and for that purpose, (i) can be read as (ii).
  • test methods are examples for indicating that usefulness of a medicament based on the aforementioned combination can be demonstrated on the basis of the prophylactic and/or therapeutic effect on, for example, glaucoma, chronic obstructive pulmonary disease, bronchial asthma, and spinal cord injury, and the methods are not intended to indicate that the usefulness of the medicament based on the combination is limited to these applications.
  • a medicament based on the aforementioned combination is useful as a medicament for prophylactic and/or therapeutic treatment of glaucoma.
  • usefulness of (i) can be confirmed by a result obtained by evaluation of (i) in the aforementioned test methods.
  • a medicament based on the combination such as enhancement of an intraocular pressure reducing action, and extension of duration of an intraocular pressure reducing action, can be confirmed by a result obtained by evaluating each compound combined with each jointly-used drug, for example, a prostaglandin-relating agent such as isopropylunoprostone and latanoprost, a carbonic anhydrase inhibitor such as dorzolamide hydrochloride, brinzolamide hydrochloride, and acetazolamide hydrochloride, an adrenergic receptor blocker such as bunazosin hydrochloride, timolol maleate, carteolol hydrochloride, befunolol hydrochloride, betaxolol hydrochloride and nipradilol hydrochloride.
  • a prostaglandin-relating agent such as isopropylunoprostone and latanoprost
  • a carbonic anhydrase inhibitor such as dorzolamide hydro
  • a medicament based on the aforementioned combination is useful as a medicament for prophylactic and/or therapeutic treatment of chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • a ⁇ -adrenergic receptor stimulant such as salbutamol sulfate, terbutaline sulfate, fenoterol hydrobromide, formoterol fumarate, and salmeterol xinafoate
  • an anticholinergic agent such as tiotropium bromide, ipratropium bromide, and oxitropium bromide
  • a xanthine derivative such as theophylline and aminophylline
  • a steroid such as beclometasone dipropionate, fluticasone propionate, and budesonide
  • a medicament based on the aforementioned combination is useful as a medicament for prophylactic and/or therapeutic treatment of bronchial asthma.
  • usefulness of (i) can be confirmed by a result obtained by evaluation of (i) in the aforementioned test methods.
  • a ⁇ -adrenergic receptor stimulant such as salbutamol sulfate, terbutaline sulfate, fenoterol hydrobromide, formoterol fumarate, and salmeterol xinafoate
  • a steroid such as beclometasone dipropionate, fluticasone propionate, and budesonide
  • a lipid mediator inhibitor such as seratrodast, ramatroban, ozagrel hydrochloride, pranlukast, montelukast sodium, and zafirlukast and the like.
  • a medicament based on the aforementioned combination is useful as a medicament for prophylactic and/or therapeutic treatment of spinal cord injury.
  • usefulness of (i) can be confirmed by a result obtained by evaluation of (i) in the aforementioned test methods.
  • higher usefulness of a medicament based on the combination can be confirmed by a result obtained by evaluating each compound combined with each jointly-used drug, for example, a steroid such as methylprednisolone succinate, a cannabinoid such as cannabinol and tetrahydrocannabinol, 4-aminopyridine and the like.
  • the aforementioned medicament based on the combination include, for example, a medicament comprising (i) and a jointly-used drug which are simultaneously administered, and a medicament comprising (i) and a jointly-used drug which are administered with an interval period within which each efficacy is expected. Further, a medicament prepared in a single form in which (i) and a jointly-used drug are mixed, and a medicament comprising (i) and a jointly-used drug which are prepared in separate forms are also included. Furthermore, a medicament wherein (i) and a jointly-used drug are administered via the same route, and a medicament wherein (i) and a jointly-used drug are separately administered are also included.
  • a mixing ratio of (i) and a jointly-used drug, a form of (i) and a jointly-used drug after mixing wherein (i) and the jointly-used drug are prepared in a single form and the like can be suitably determined depending on a purpose of administration, an administration route, a disease to be treated, symptoms, physicochemical properties of the drug, easiness of administration and the like, and a dose thereof can be suitably chosen on the basis of, for example, clinically used doses of (i) and the jointly-used drug.
  • the aforementioned pharmaceutical additives may be used in addition to (i) and the jointly-used drug to prepare a pharmaceutical composition, and a preferred form such as oral agents, injections (solution, suspension and the like), fusion drips, inhalants, suppositories, transdermally absorbed agents (e.g., tapes), ointments, ophthalmic solutions, ophthalmic ointments, ophthalmic membrane adherent agents and the like can be prepared and used.
  • a preferred form such as oral agents, injections (solution, suspension and the like), fusion drips, inhalants, suppositories, transdermally absorbed agents (e.g., tapes), ointments, ophthalmic solutions, ophthalmic ointments, ophthalmic membrane adherent agents and the like can be prepared and used.
  • the medicament characterized by comprising (i) and a jointly-used drug in combination can be used as an agent for prophylactic and/or therapeutic treatment of various diseases.
  • the diseases are preferably those relating to contraction of various cells, and among the diseases relating to contraction of various cells, preferred examples include glaucoma, bronchial asthma, or chronic obstructive pulmonary disease.
  • any kind of the medicament characterized by comprising (i) and a jointly-used drug in combination is also preferred as an agent for prophylactic and/or therapeutic treatment of diseases relating to migration of various cells, and the disease is also preferably bronchial asthma, or chronic obstructive pulmonary disease among the diseases relating to migration of various cells.
  • any kind of the medicament characterized by comprising (i) and a jointly-used drug in combination is also preferred as an agent for prophylactic and/or therapeutic treatment of diseases relating to morphological change of various cells.
  • the disease is more preferably a neurological disorder, and the neurological disorder is more preferably spinal cord injury.
  • the compound (i) has an intraocular pressure reducing action as demonstrated in Test Example 4, and it has been confirmed that the medicaments of [1], [2], and [3] mentioned above induce enhancement of the intraocular pressure reducing action, extension of duration of the intraocular pressure reducing action and the like compared with a pharmaceutical composition containing (i) alone as an active ingredient as demonstrated in Test Example 13. Thus, they are preferred as agents for therapeutic and/or prophylactic treatment of glaucoma. Further, a medicament comprising (i) and an agent for therapeutic and/or prophylactic treatment of glaucoma in combination is also preferred.
  • drugs having an intraocular pressure reducing action drugs having an optic nerve protective action, drugs having an intraocular pressure reducing action, and/or an optic nerve protective action and the like are known.
  • the drug having an intraocular pressure reducing action is not particularly limited so long as the drug has an intraocular pressure reducing action.
  • Examples include adrenergic receptor stimulants, prostaglandin-related agents, carbonic anhydrase inhibitors (also abbreviated as CAI), adrenergic receptor blockers, cholinesterase inhibitors, calcium antagonists ( AI Report, Cima Science Journal, 2002 ), Rho kinase inhibitors ( Honjo, M. et al., Invest. Ophthalmol. Vis. Sci., 42 (1), pp.137-44 (2001) ; Honjo, M. et al., Arch. Ophthalmol. 119 (8), pp.1171-8 (2001) ), angiotensin II receptor antagonists ( Inoue, T. et al., Current Eye Res., 23 (2), pp.
  • any one or more of these drugs can be used.
  • two or more kinds of jointly-used drugs (the same shall apply to (i) and (ii)) are selected, two or more kinds of the drugs may be selected from drugs belonging to the same classification, or one or more kind of the drugs may be selected from drugs belonging to each of different classifications.
  • the drugs are preferably selected from those belonging to different classifications.
  • the drug having an intraocular pressure reducing action one or more kinds of drugs among prostaglandin-related agents, carbonic anhydrase inhibitors, and adrenergic receptor blockers are preferred. This medicament is preferred as an agent for therapeutic and/or prophylactic treatment of glaucoma.
  • the drug having an optic nerve cell protective action means a drug having an action of protecting optic nerves, and examples include drugs having an action of protecting optic nerve cells based on an action of suppressing cell death as well as an action of improving eyeground vascular flow.
  • the action of suppressing cell death of optic nerve cells can be confirmed as an action of suppressing cell death induced via a glutamate receptor in an exo vivo culture system using retinal nerve cells extracted from a rat or the like by adding NMDA ( Hahn et al., Proc. Natl. Acad. Sci. USA, 85, 6556.
  • the action of improving the eyeground vascular flow can be confirmed by, for example, quantitatively analyzing change of the eyeground vascular flow in human, rabbit, monkey, or the like administered with the drug using the laser speckle method ( Tamaki, Y. et al., Surv. Ophthalmol., 42 (Suppl. 1), S52-S63. (1997 )).
  • the drug having an optic nerve protective action include adrenergic receptor stimulants ( Wheeler, LA. et al., Eur. J. Ophthalmol., 11 (Suppl. 2) 403-11. (2001 )), adrenergic receptor blockers ( Wood, JP., et al., Exp. Eye Res.
  • drugs having either of the intraocular pressure reducing action and the optic nerve protective action drugs both having the intraocular pressure reducing action and the optic nerve protective action as a single agent are also known.
  • examples of such drugs include, for example, adrenergic receptor stimulants, prostaglandin-related agents, carbonic anhydrase inhibitors, adrenergic receptor blockers, calcium antagonists and the like, and any one or more these drugs may be used.
  • the drugs having an intraocular pressure reducing action and/or drugs having an optic nerve protective action can be divided into the aforementioned drugs having an intraocular pressure reducing action, drugs having an optic nerve protective action, and drugs having both of an intraocular pressure reducing action and an optic nerve protective action as a single agent.
  • drugs having an intraocular pressure reducing action and/or drugs having an optic nerve protective action include, for example, one or more of adrenergic receptor stimulants, prostaglandin-related agents, carbonic anhydrase inhibitors, adrenergic receptor blockers, cholinesterase inhibitors, calcium antagonists, Rho kinase inhibitors, angiotensin II receptor antagonists, NMDA receptor blockers and the like.
  • preferred examples include one or more of prostaglandin-related agents, carbonic anhydrase inhibitors, adrenergic receptor blockers, NMDA receptor blockers and the like.
  • the adrenergic receptors include, for example, those of ⁇ 1A-subtype considered to be involved in control of constriction and relaxation of various smooth muscles, ⁇ 1B-subtype, ⁇ 1D-subtype, ⁇ 2A-subtype, ⁇ 2B-subtype, ⁇ 2C-subtype, ⁇ 1-subtype, ⁇ 2-subtype, and ⁇ 3-subtype ( Kurose et al., Protein Nucleic Acid Enzyme, Vol. 42, No. 3, pp.316-26. (1997 )).
  • the adrenergic receptor stimulants means a medicament that acts as an agonist against at least one of the aforementioned adrenergic receptors , and has an regulatory action on various smooth muscles.
  • Examples of the regulatory action on various smooth muscles include, for example, an intraocular pressure reducing action, and a tracheal dilational action.
  • the medicaments herein refer to mean those exhibiting an intraocular pressure reducing action.
  • those selectively acting on ⁇ -receptors may be described as ⁇ -stimulants
  • those selectively acting on ⁇ 2-receptors may be described as ⁇ 2-stimulants and the like.
  • examples of the adrenergic receptor stimulants include, for example, non-selective sympathetic nerve stimulants, ⁇ 1-stimulants, and ⁇ 2-stimulants.
  • Epinephrine, dipivefrin U.S.
  • Patent No. 3,809,714 apraclonidine ( U.S. Patent No. 4,517,199 ), brimonidine ( U.S. Patent No. 4,517,199 ), and physiologically acceptable salts thereof are preferred, and epinephrine hydrochloride, dipivefrin hydrochloride, apraclonidine, and brimonidine tartrate are preferred. Any one of these drug is preferred, or any two or more are also preferred.
  • the prostaglandin-related agents are roughly classified into prostaglandin receptor (FP receptor) binding prostaglandins ( Richard, MB.et al., Annu. Rev. Pharmacol. Toxicol., 41, pp.661-90. (2001 )), and metabolic type prostaglandins. In addition, derivatives thereof such as isopropylunoprostone can be exemplified.
  • the prostaglandin receptor (FP receptor) binding prostaglandins are prostaglandins having an ability to bind with an FP receptor, and generally, they are often naturally-occurring prostaglandins or compounds having similar structures.
  • the prostaglandin-related agents preferably further exhibit an intraocular pressure reducing action, and preferably have a curative effect for glaucoma.
  • naturally occurring prostaglandins include, for example, prostaglandin F 2 ⁇ and the like.
  • the FP receptor binding prostaglandins having a structure similar to that of naturally occurring prostaglandins include, for example, latanoprost, travoprost, bimatoprost, tafluprost and the like.
  • the metabolic type prostaglandins mean compounds produced by metabolism of the FP receptor binding prostaglandins in the living bodies. Therefore, in the present invention, as the prostaglandin-related agents, isopropylunoprostone ( U.S. Patent No.
  • the carbonic anhydrase inhibitors mean isozymes of carbonic anhydrase having at least type II and/or type IV enzyme inhibitory action.
  • the carbonic anhydrase inhibitors include, for example, dorzolamide ( European Patent Publication No. 296879 ), brinzolamide ( U.S. Patent No. 5,378,703 ), acetazolamide ( U.S. Patent No. 2,554,816 ), and physiologically acceptable salts thereof, and dorzolamide hydrochloride, brinzolamide hydrochloride, and acetazolamide hydrochloride are preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • the adrenergic receptors are the same as those mentioned above.
  • the adrenergic receptor blockers means drugs that act as an antagonist against at least one adrenergic receptor, and have an action of regulating various smooth muscles.
  • the action of regulating various smooth muscles preferably means an action exhibiting an intraocular pressure reducing action.
  • they may be described as ⁇ -blockers, ⁇ -blockers, or ⁇ ⁇ -blockers.
  • Examples of the adrenergic receptor blockers include, for example, ⁇ -blockers, ⁇ -blockers, and ⁇ ⁇ -blockers, bunazosin ( British Patent Application Publication No. 1398455 ), timolol ( U.S. Patent No.
  • cholinesterase inhibitors include, for example, demecarium, physostigmine ( U.S. Patent No. 4,791,107 ), echothiophate, and physiologically acceptable salts thereof, and physostigmine sulfate and the like are preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • the calcium antagonists include, iganidipine ( U.S. Patent No. 2,554,.16 ), lomerizine (Japanese Patent Unexamined Publication (KOKAI) No. 60-222472 ), and physiologically acceptable salts thereof, and iganidipine hydrochloride, and lomerizine hydrochloride are also preferred.
  • Rho kinase inhibitors include, for example, (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane (Y-27632), (+)-trans-N-(pyrrolo[1H[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide (Y-39983) (International Patent Publication WO02/083175 ), HA-1077 ( Nagumo, H.
  • the angiotensin II receptors include those of AT 1A , AT 1B , AT 2 , AT 3 , and AT 4 subtypes, which bind to angiotensin II to be involved in blood pressure regulating action and the like, and the angiotensin II receptor antagonists mean drugs having a binding activity at least to AT 1 receptor, which antagonizes against angiotensin II, to attenuate the action of angiotensin II.
  • the angiotensin II receptor antagonists include, for example, olmesartan (CS-088) ( U.S. Patent No. 5,616,599 ), and physiologically acceptable salts thereof, and olmesartan is preferred.
  • NMDA receptor antagonists include, for example, memantine ( U.S. Patent No. 4,122,193 ), and physiologically acceptable salts thereof, and memantine hydrochloride is preferred. Any one of these drugs is preferred, or any two or more are also preferred. Moreover, a method for therapeutic and/or prophylactic treatment of glaucoma, which uses any of the medicaments mentioned above is also preferred.
  • one to ten drops preferably one or two drops (the volume of one drop is about 50 ⁇ L), as a dose for one administration, can be preferably administered about 1 to 6 times a day.
  • the object of the administration is human, for example, the jointly-used drug is generally used preferably in an amount of 0.001 to 100 parts by weight with 1 weight part of (i).
  • the jointly-used drug is used in an amount of, for example, 0.00001 part by weight or more, preferably 0.0001 part by weight or more, more preferably 0.001 part by weight or more, further preferably 0.01 part by weight or more, or 0.1 part by weight or more, or 0.5 part by weight or more, based on 1 part by weight of (i).
  • the jointly-used drug is generally used in an amount of 100 parts by weight or less, preferably 50 parts by weight or less, more preferably 25 parts by weight or less, or 10 parts by weight or less, or 5 parts by weight or less.
  • chronic obstructive pulmonary disease which is one of the diseases relating to constriction of various cells, or diseases relating to migration of various cells, (i) has a respiratory tract constriction suppressing action as shown in Test Example 3, neutrophil migration inhibitory action as shown in Test Example 6, respiratory tract inflammation suppressing action as shown in Test Example 7, and lung inflammation suppressing action as shown in Test Example 8, and therefore the medicaments of [11] and [12] mentioned above are preferred as a therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease.
  • examples of the drugs having a tracheal dilational action include, for example, ⁇ 2-adrenergic receptor stimulants, neurokinin (also abbreviated as NK) antagonists, xanthine derivatives, anticholinergic agents, phosphodiesterase inhibitors (Masakazu Ichinose, Respiratory Disease New Approach 8, Obstructive Pulmonary Diseases, MEDICAL VIEW, 2002), Rho kinase inhibitors ( Iizuka, K. et al., Eur. J. Pharmacol., 406 (2), pp.273-9. (2000 )); Japanese Patent Unexamined Publication (KOKAI) No.
  • a medicament comprising (i) and any one or two of drugs among a ⁇ 2 adrenergic receptor stimulant, an NK antagonist, a xanthine derivative, an anticholinergic agent, and a phosphodiesterase inhibitor in combination is also preferred.
  • the anti-inflammatory action means an action of improving inflammation image of chronic obstructive pulmonary disease
  • examples include, for example, suppression of infiltration of leucocytes such as neutrophiles and mast cells into the lung ( Gizycki, ML. et al., Thorax, 57 (9), 799-803. (2002 )), suppression of degradation of tissue elastin or collagen ( Culpitt, SV. et al., Am. J. Respir. Crit. Care Med., 165, 1371-76 (2002) ), suppression of production of cytokines such as TNF- ⁇ , IL-8, and GM-CSF ( Profita, M.
  • drugs having an anti-inflammatory action include, for example, steroids, xanthine derivatives, phosphodiesterase inhibitors, elastase inhibitors and the like, and any one or more of these drugs can be used.
  • a medicament comprising (i) and any one or more drugs among a steroid, a xanthine derivative, a phosphodiesterase inhibitor, and an elastase inhibitor is also preferred.
  • drugs having either one of the tracheal dilational action and the anti-inflammatory action drugs having both a tracheal dilational action and an anti-inflammatory action as a single agent are also known. Examples of such drugs include xanthine derivatives, and phosphodiesterase inhibitors, and any one or two or more of these drugs can be used.
  • the drugs having a tracheal dilational action and/or an anti-inflammatory action can be divided into the aforementioned drugs having a tracheal dilational action, drugs having an anti-inflammatory action, and drugs having both a tracheal dilational action and an anti-inflammatory action as a single agent.
  • drugs for example, any one or more of a ⁇ 2-adrenergic receptor stimulant, an NK antagonist, a xanthine derivative, an anticholinergic agent, a phosphodiesterase inhibitor, a Rho kinase inhibitors, a steroid, an elastase inhibitor, and a leukotriene receptor antagonist can be used, and any one or more of a ⁇ 2.
  • adrenergic receptor stimulant a xanthine derivative, an anticholinergic agent, a phosphodiesterase inhibitors, a steroid, and a leukotriene receptor antagonist are preferably used. These medicaments are preferred as a therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease.
  • the medicaments of [15] and [16] mentioned above are also preferred as a therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease from another aspect.
  • examples of preferred ⁇ 2-adrenergic receptor stimulants include, for example, salbutamol, terbutaline, fenoterol, formoterol, salmeterol ( International Patent Publication WO95/01324 ), and physiologically acceptable salts thereof, and salbutamol sulfate, terbutaline sulfate, fenoterol hydrobromide, formoterol fumarate, and salmeterol xinafoate are also preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • NK antagonists include, for example, talnetant, and physiologically acceptable salts thereof, and talnetant and the like are also preferred ( U.S. Patent No. 5,811,553 ). Any one of these drugs is preferred, or any two or more are also preferred.
  • the xanthine derivatives means structural analogues of xanthine.
  • preferred xanthine derivatives include, for example, theophylline, aminophyllines, and physiologically acceptable salts thereof, and theophylline, and aminophylline are preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • the anticholinergic agents means agents that acts as an antagonist against at least the M3 subtype among the three subtypes (M1, M2, M3) of muscarine receptors, and exhibit a tracheaectasy action ( Masakazu Ichinose, Respiratory Disease New Approach 8, Obstructive Pulmonary Disease, pp.68-76, 2003, Medical View ).
  • Examples of preferred anticholinergic agents include, for example, tiotropium ( U.S. Patent No. 5,610,163 ), ipratropium ( U.S. Patent No. 3,505,337 ), oxitropium ( Banholzer, VR. et al., Arzneistoffforschung, 35 (1A) 217-28. (1985 )), and pharmacologically acceptable salts thereof. Any one of these drugs is preferred, or any two or more are also preferred. Examples of the aforementioned physiologically acceptable salts include tiotropium bromide, ipratropium bromide, and oxitropium bromide (Ba253).
  • steroids used as agents for therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease
  • steroids that can be prepared as inhalants are preferred.
  • beclometasone, fluticasone ( British Patent No. 2088877 ), budesonide (Japanese Patent Unexamined Publication (KOKAI) No. 2000-128897 ), and physiologically acceptable salts thereof are preferred, and beclometasone dipropionate, fluticasone propionate, and budesonide are preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • preferred examples of the PDE inhibitors include, for example, PDE4 inhibitors, and preferred examples include, for example, cilomilast ( Griswold, DE. et al., J. Pharmacol. Exp. Ther., 287 (2), 705-11. (1998 )), roflumilast ( Bundschuh, DS. et al., J. Pharmacol. Exp. Ther., 297 (1) 280-90. (2001 ), arophylline ( European Patent Publication No. 0435811 ), and physiologically acceptable salts thereof.
  • preferred examples include cilomilast, roflumilast, and arophylline. Any one of these drugs is preferred, or any two or more are also preferred.
  • elastase inhibitors include, for example, sivelestat ( Kawabata, K. et al., Biochem. Biophys. Res. Commun., 177 (2), 814-20. (1991 ), midesteine (MR889) ( Baici, A. et al., Biochem. Pharmacol., 39 (5), 919-24 (1990) ), physiologically acceptable salts thereof and the like. Sivelestat sodium, and midesteine are also preferred. Any one of these drugs is preferred, or any two or more are also preferred. In the present invention, the leukotriene receptor antagonist will be described later.
  • the antibiotics for example, macrolide antibiotics are preferred, and preferred examples include erythromycin and the like.
  • the expectorants for example, N-acetylcysteine and the like are preferred.
  • the aforementioned medicaments When used as an inhalant, they can be administered about 1 to 6 times a day by spraying a spraying amount once to 10 times, preferably once or twice, for each administration.
  • an object of the administration is a human, for example, (i) is generally preferably used in an amount of 0.0 1 ⁇ g to 100 mg per a single spraying.
  • the jointly-used drug is used in an amount of, for example, 0.0001 ⁇ g or more, preferably 0.001 ⁇ g or more, more preferably 0.01 ⁇ g or more, or 0.1 ⁇ g or more, or 0.5 ⁇ g or more.
  • the upper limit of the amount of the jointly-used drug is not also particularly limited, it is generally used in an amount of 100 mg or less, preferably 10 mg or less, more preferably 5 mg or less, or 1 mg or less, or 500 ⁇ g or less.
  • the medicament when used as, for example, an oral agent or an injection, a single dose can be administered about once to 10 times a day.
  • an object of the administration is a human, for example, (i) is generally used preferably in an amount of 0.0001 to 5000 mg/kg at one time. More specifically, although the lower limit of the amount of the jointly-used drug is not particularly limited so long as the effect of the present invention is exhibited, the jointly-used drug is used in an amount of, for example, 0.000001 mg/kg or more, preferably 0.00001 mg/kg or more, more preferably 0.0001 mg/kg or more, or 0.001 mg/kg or more, or 0.01 mg/kg or more, or 0.1 mg/kg or more.
  • the upper limit of the amount of the jointly-used drug is not also particularly limited, it is generally used in an amount of 5000 mg/kg or less, preferably 1000 mg/kg or less, more preferably 100 mg/kg or less, or 50 mg/kg or less, or 20 mg/kg or less.
  • bronchial asthma which is one of the diseases relating to constriction of various cells, or the diseases relating to migration of various cells, (i) has a respiratory tract constriction suppressing action as shown in Test Example 3, neutrophil migration inhibitory action as shown in Test Example 6, and respiratory tract inflammation suppressing action as shown in Test Example 7.
  • a medicament comprising (i) and any one or more of a ⁇ 2-adrenergic receptor stimulant, an anticholinergic agent, a Rho kinase inhibitor, a steroid, a xanthine derivative, a phosphodiesterase inhibitor, a chemical mediator release inhibitor, an antihistamine, a lipid mediator inhibitor, a leukotriene receptor antagonist, and a Th2 cytokine production inhibitor in combination is preferred as agent for therapeutic and/or prophylactic treatment of bronchial asthma, and the medicaments of [13] and [15] to [20] mentioned above are preferred as agents for therapeutic and/or prophylactic treatment of bronchial asthma.
  • ⁇ 2- adrenergic receptor stimulants anticholinergic agents, Rho kinase inhibitors, steroids, xanthine derivatives, phosphodiesterase inhibitors, and leukotriene receptor antagonists, for example, those containing the same active ingredient as that of those used for therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease may be used. Any one of these drugs is preferred, or any two or more are also preferred.
  • the chemical mediator means, for example, a substance which is intracellularly stored in mast cells and/or basophiles, and released upon a stimulation to the cells to cause various phenomena such as increased vascular permeability, contraction of various smooth muscles, increased mucous secretion, and increased migration of immune cells, a substance which is produced from a lipid such as arachidonic acid, and released upon a stimulation to the cells to cause various phenomena such as increased vascular permeability, contraction of various smooth muscles, increased mucous secretion, and increased migration of immune cells (lipid mediator), or the like.
  • the former substances include histamine, serotonin, leukotriene and the like, and examples of the latter include leukotrienes, thromboxane, prostaglandin D2, platelet activating factor (PAF) and the like ( Ogura T. et al., Key Word 1994-'95, Sentan Igaku-Sha, 1994 ).
  • the chemical mediator release inhibitors mean those inhibiting the release of the chemical mediators stored in mast cells and/or basophiles upon a stimulation to the cells.
  • examples of the chemical mediator release inhibitors include, for example, cromolyn (Japanese Patent Unexamined Publication (KOKAI) No.
  • ibudilast Japanese Patent Publication (KOKOKU) No. 52-29318
  • tranilast Japanese Patent Unexamined Publication (KOKAI) No. 5-097825
  • pemirolast Japanese Patent Unexamined Publication (KOKAI) No. 2003-073378
  • physiologically acceptable salts thereof and the like and sodium cromoglicate, ibudilast, tranilast, and pemirolast potassium are more preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • the lipid mediator inhibitors mean drugs which attenuate physiological actions mediated by the lipid mediators by a mechanism of inhibiting a function of an enzyme essential for the biosynthesis of the aforementioned chemical mediators under physiological conditions, or a mechanism of antagonistically inhibiting binding of the lipid mediators to a receptor thereof, and examples include thromboxane-A2 synthetase inhibitors, thromboxane A2 receptor antagonists, leukotriene receptor antagonists and the like.
  • the thromboxane-A2 synthetase inhibitors mean those inhibiting a function of an enzyme catalyzing generation of thromboxane A2 from prostaglandin H2.
  • the thromboxane receptor antagonists mean drugs that antagonistically inhibit binding of thromboxane A2 to thromboxane A2 receptor to attenuate the physiological activities thereof.
  • the leukotriene receptors include those of BLT1, BLT2, CysLT1, and CysLT2 subtypes ( Izumi, T. et al., J. Biochem., 132, pp.1-6. (2002 )), and the leukotriene receptor antagonists mean drugs that antagonistically inhibit binding of leukotriene B 4 , leukotriene C 4 , leukotriene D 4 , or leukotriene E 4 to at least one of the aforementioned receptor subtypes to attenuate the physiological functions thereof.
  • examples of the lipid mediator inhibitors include thromboxane-A2 synthetase inhibitors, thromboxane A2 receptor antagonists, and leukotriene antagonists are preferred, and for example, seratrodast, ramatroban ( European Patent No. 242518 ), ozagrel ( U.S. Patent No. 4,226,878 ), pranlukast ( European Patent Publication No. 0173516 ), montelukast ( European Patent No. 480717 ), zafirlukast ( U.S. Patent No.
  • the antihistamines mean those antagonistically inhibiting binding of histamine to at least the histamine H1 receptor to attenuate the physiological functions thereof.
  • examples of the antihistamines include, for example, epinastine (Japanese Patent Publication (KOKOKU) No. 3-66311 ), ketotifen, fexofenadine ( International Patent Publication WO97/23213 ), oxatomide (Japanese Patent Publication (KOKOKU) No. 62-31707 ), cetirizine ( British Patent No. 2225321 ), olopatadine ( U.S. Patent No.
  • Th2 cytokines mean interleukin-4, interleukin-5, interleukin-6, interleukin-10, interleukin-13 and the like, which are produced by type 2 helper T cells
  • the Th2 cytokine production inhibitors mean drugs that regulate the production of at least one of the cytokines.
  • the Th2 cytokine production inhibitors include, for example, suplatast (Japanese Patent Publication (KOKOKU) No. 3-70698 ), and physiologically acceptable salts thereof, and suplatast tosilate is preferred. Any one of these drugs is preferred, or any two or more are also preferred.
  • the aforementioned medicaments When used as an inhalant, they can be administered about 1 to 6 times a day by spraying a spraying amount once to 10 times, preferably once or twice, for a single administration.
  • an object of the administration is a human, for example, (i) is generally used preferably for each spraying in an amount of 0.01 ⁇ g to 100 mg.
  • the lower limit of the amount of the jointly-used drug is not particularly limited so long as the effect of the present invention is exhibited, the jointly-used drug is used in an amount of, for example, 0.0001 ⁇ g or more, preferably 0.001 ⁇ g or more, more preferably 0.01 ⁇ g or more, or 0.1 ⁇ g or more, or 0.5 ⁇ g or more.
  • the upper limit of the amount of the jointly-used drug is not also particularly limited, it is generally used in an amount of 100 mg or less, preferably 10 mg or less, more preferably 5 mg or less, or 1 mg or less, or 500 ⁇ g or less.
  • the medicament is used as, for example, an oral agent or an injection, a single dose can be administered about once to 10 times a day.
  • an object of the administration is a human, for example, (i) is generally used preferably in an amount of 0.0001 to 5000 mg/kg at one time.
  • the jointly-used drug is used in an amount of, for example, 0.000001 mg/kg or more, preferably 0.00001 mg/kg or more, more preferably 0.0001 mg/kg or more, or 0.001 mg/kg or more, or 0.01 mg/kg or more, or 0.1 mg/kg or more.
  • the upper limit of the amount of the jointly-used drug is not also particularly limited, the drug is generally used in an amount of 5000 mg/kg or less, preferably 1000 mg/kg or less, more preferably 100 mg/kg or less, or 50 mg/kg or less, or 20 mg/kg or less.
  • the compound (i) has a neurite outgrowth activity as shown in Test Example 5, and neutrophil migration inhibitory action as shown in Test Example 6. Accordingly, the medicaments of [15], and [22] to [25] mentioned above are preferred as agents for therapeutic and/or prophylactic treatment of spinal cord injury, which is one of traumatic nerve injuries, among neurological disorders, which constitute a class of diseases relating to morphological change of various cells.
  • a medicament comprising (i) and a drug having a central nerve regeneration action in combination is also preferred as an agent for therapeutic and/or prophylactic treatment of spinal cord injury.
  • the antibiotics used for therapeutic and/or prophylactic treatment of spinal cord injury for example, those comprising the same active ingredient as those used for therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease.
  • the steroids used for therapeutic and/or prophylactic treatment of spinal cord injury may comprise the same or different active ingredient as those used for therapeutic and/or prophylactic treatment of chronic obstructive pulmonary disease.
  • Steroids with which an oral agent and an injection can be prepared are preferred.
  • the steroids for example, methylprednisolone, and physiologically acceptable salts thereof are preferred, and methylprednisolone succinate and the like are preferred.
  • cannabinoids mean cannabinol and structural analogues thereof, and for example, cannabinol, tetrahydrocannabinol, physiologically acceptable salts thereof and the like are preferred.
  • the potassium channel blockers mean those acting on at least one of the voltage-dependent potassium channels to inhibit the functions thereof, and for example, 4-aminopyridine, physiologically acceptable salts thereof and the like are preferred.
  • the hypoxanthine derivatives mean structural analogues of hypoxanthine, for example, leteprinim (AIT-082) ( U.S. Patent No. 6,288,069 ), and physiologically acceptable salts thereof are preferred, and leteprinim potassium is preferred.
  • regeneration of central nerve means a neurite outgrowth action for central nerve cells, action of neutralizing central nerve axonal growth inhibitor and the like
  • drugs having a central nerve regeneration action include, for example, NGF (nerve growth factor), Rho kinase inhibitors ( Tanaka, T. et al., J. Cell Biol., 158 (2), pp.321-329 (2002) ), BDGF (brain-derived nerve growth factor, Kishino, A., et al., Exp. Neurol., 144 (2), pp.273-86 (1997) ), FGF (fibroblast growth factor, Rabchevsky, AG., et al., J. Neurotrauma., 16(9), pp.817-30.
  • the central nerve axonal growth inhibitors means substances that inhibit axonal growth of central nerves under physiological conditions, and examples include myelin-related proteins, substances originated from glial scars formed in injury lesions (semaphorin, chondroitin sulfate and the like) and the like ( Nakamura M. et al., Journal of Spine and Spinal Cord, Vol. 16, No. 4, pp.284-290. (2003 )). Further, a method for therapeutic and/or prophylactic treatment of spinal cord injury using any of the medicaments mentioned above is also preferred.
  • the medicament when used as, for example, an oral agent or an injection, a single dose can be administered about once to 10 times a day.
  • the object of the administration is human, for example, (i) is generally used preferably in an amount of 0.0001 to 5000 mg/kg at one time. More specifically, although the lower limit of the amount of the jointly-used drug is not particularly limited so long as the effect of the present invention is exhibited, the jointly-used drug is used in an amount of, for example, 0.000001 mg/kg or more, preferably 0.00001 mg/kg or more, more preferably 0.0001 mg/kg or more, or 0.001 mg/kg or more, or 0.01 mg/kg or more, or 0.1 mg/kg or more.
  • the upper limit of the amount of the jointly-used drug is not also particularly limited, it is generally used in an amount of 5000 mg/kg or less, preferably 1000 mg/kg or less, more preferably 100 mg/kg or less, or 50 mg/kg or less, or 20 mg/kg or less.
  • Elution was generally performed at a flow rate of 2 ml/minute using a linear gradient of 5 to 100% (v/v) Solution B [acetonitrile containing 0.1% (v/v) acetic acid] in Solution A [water containing 0.1% (v/v) acetic acid] from 0 minute to 5 minutes as the solvent.
  • the compounds of the examples are shown in Tables 1 to 7 mentioned later (in the tables, numerals indicated in the columns of "Exp. No.” are example numbers, Me represents methyl, and Bn represents benzyl).
  • the compounds of Table 1 have the structure of the following formula (1-A)
  • the compounds of Table 2 have the structure of the following formula (1-B)
  • the compounds of Table 3 have the structure of the following formula (1-C)
  • the compounds of Table 4 have the structure of the following formula (1-D)
  • the compounds of Table 5 have the structure of the following formula (1-E)
  • the compounds of Table 6 have a structure of the following formula (1-F)
  • the compounds of Table 7 have the structure of the following formula (1-G), respectively.
  • Example 1-2 1-Methyl-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-3 1-(Cyclopentylmethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-3 The compound of Example 1-3 can be prepared by Method A or Method B mentioned below.
  • Example 1-6 The compound of Example 1-6 can be prepared by Method A or Method B mentioned below .
  • Example 1-7 3-[3-(2,3-Dihydro-1,5-diazaphenalen-1-yl)piperidin-1-yl]propanoic acid
  • Example 1-12 1-(4-Hydroxycyclohexyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-13 1-(2-Methoxyethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-14 1-(2-Pivaloyloxyethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-15 1-(2-Acetylthioethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-16 1-(2-Thioethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-17 1-(2-Aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-18 1-(3-Aminopropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • the aqueous layer was extracted 3 times with chloroform (20 ml for each time), and the combined organic layer was successively washed with water (30 ml), and saturated brine (30 ml) in this order, and dried over anhydrous magnesium sulfate.
  • the organic layer was filtered through Celite, and then the solvent was evaporated under reduced pressure.
  • the reaction mixture was cooled to 0°C, neutralized with 2 N aqueous sodium hydroxide (pH 7.5), and extracted 3 times with ethyl acetate (30 ml for each time).
  • Example 1-21 2-[3-(2,3-Dihydro-1,5-diazaphenalen-1-yl)piperidin-1-yl]-1,3-propanediamine
  • Example 1-22 1-(2-Acetaminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-24 1-[2-(2-Acetaminoacetamino)ethyl]-3-(2,3-dihydro-1,5-diazaphenalen- 1-yl)piperidine
  • Example 1-25 1- ⁇ 2-[2-(Dimethylamino)acetaminoethyl] ⁇ -3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-26 1-(2-Methanesulfonylaminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1-17 1-(2-Aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-17 was used to react with methanesulfonic anhydride according to the method described in Example 1-22 to obtain the title compound. MS (m/z): 375 (MH+)
  • Example 1-28 1-(4-Acetaminocyclohexyl)-3-(2,3-dihydro-1,5-diazaphenalen- 1-yl)piperidine
  • Example 1-(4-Aminocyclohexyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-27 was used to react with acetic anhydride according to the method described in Example 1-22 to obtain the title compound. MS (m/z): 393 (MH+)
  • Example 1-33 2-(Dimethylamino)ethyl N- ⁇ 2-[3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidin-1-yl]ethyl ⁇ carbamate
  • Example 1-34 2-[3-(2,3-Dihydro-1,5-diazaphenalen-1-yl)piperidin-1-yl]ethyl cyclopentylcarbamic acid
  • Example 1-36 1- ⁇ 2-[3-(2,3-Dihydro-1,5-diazaphenalen-1-yl)piperidine]ethyl ⁇ -azetidin-2-one
  • Example 1-37 1-Acetyl-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine
  • Example 1 The compounds of Examples 1-38 to 1-72 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1, Step D to perform alkylation or reductive alkylation according to the method described in Example 1-3, Method A or Method B, or Example 1-12.
  • Examples 1-73 and 1-74 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1, Step D to perform condensation according to the method described in Example 1-5.
  • Examples 1-75 to 1-92 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1, Step D to perform alkylation according to the method described in Example 1-6.
  • Examples 1-94 to 1-100 were obtained by using 1-(2-hydroxyethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-10, 1-(3-hydroxypropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-81, or 1-(4-hydroxybutyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-87 to perform active esterification and then condensation with an amine according to the method described in Example 1-93.
  • Examples 1-101 and 1-102 were obtained by using 1-(3-acetylthiopropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine, or 1-(4-acetylthiobutyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine to perform hydrolysis according to the method described in Example 1-16.
  • Examples 1-103 to 1-105 were obtained by using 1-(2-hydroxyethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-10, or 1-(3-hydroxypropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-81 to perform thioesterification according to the method described in Example 1-15.
  • Examples 1-106 to 1-108 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform alkylation according to the method described in Example 1-10.
  • the compounds of Examples 1-109 to 1-124 were obtained by using 1-(2-hydroxyethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-10, 1-(3-hydroxypropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-81, or 1-(4-hydroxybutyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-87 to perform esterification according to the method described in Example 1-24.
  • Examples 1-125 to 1-136 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform alkylation, or alkylation and subsequent ureation according to the methods described in Examples 1-17 and 1-29.
  • Examples 1-137 to 1-141 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform alkylation according to the method described in Example 1-17.
  • Examples 1-142 to 1-151 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform alkylation, deprotection for the protective group, and reductive amination according to the method described in Example 1-19.
  • Examples 1-152 to 1-154 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform alkylation according to the method described in Example 1-6, Method A or Method B.
  • Examples 1-155 to 1-186 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform alkylation, deprotection for the protective group, reductive amination, and esterification according to the methods described in Example 1-19 and Example 1-24.
  • Example 1-187 The compound of Example 1-187 was obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive alkylation, and reduction according to the method described in Example 1-12.
  • the compound of Examples 1-188 was obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive alkylation, and deprotection for the protective group according to the method described in Example 1-27.
  • the compounds of Examples 1-189 to 1-191 were obtained by using 1-(3-acetaminocyclobutyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-188, or 1-(4-aminocyclohexyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-27 to perform esterification according to the method described in Example 1-28.
  • Examples 1-192 to 1-194 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive amination, and then deprotection for the protective group as required according to the method described in Example 1-12, or Example 1-27.
  • Examples 1-195 to 1-214 were obtained by using 1-(2-aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-17, 1-[2-(methylamino)ethyl]-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-142, 1-(3-aminopropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-18, 1-[3-(methylamino)propyl]-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-19, 1-(4-aminobutyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-140, 1-[2-(2-hydroxyethyl)-3
  • the compound of Examples 1-215 was obtained by using 1-(3-aminocyclobutyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-188 to perform sulfonylation according to the method described in Example 1-26.
  • the compound of Examples 1-216 was obtained by performing reductive amination with methylamine instead of the reduction of carbonyl group in Example 1-12.
  • Example 1-217 The compound of Example 1-217 was obtained by using 1-(4-aminocyclohexyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-28 to perform sulfonylation according to the method described in Example 1-26.
  • Example 1-218 The compound of Example 1-218 was obtained by performing reductive amination with dimethylamine instead of the reduction of carbonyl group in Example 1-12.
  • the compounds of Examples 1-219 to 1-240 and 1-243 to 1-294 were obtained by using 1-(2-aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-17, 1-[2-(methylamino)ethyl]-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-142, 1-(3-aminopropyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-18, or 1-[3-(methylamino)propyl]-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-19 to perform ureation according to the method described in Example 1-29, or 1-30.
  • Examples 1-241 and 1-242 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive alkylation according to the method described in Example 1-3, Method B.
  • Examples 1-295 to 1-298 and 1-300 to 1-305 were obtained by using 1-(2-aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-17 to perform thioureation according to the method described in Example 1-31 or Example 1-32.
  • Example 1-299 The compound of Example 1-299 was obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive alkylation according to the method described in Example 1-3, Method B.
  • Examples 1-306 to 1-313 were obtained by using 1-(2-aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-17 to perform carbamation according to the method described in Example 1-33.
  • Examples 1-314 and 1-315 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive alkylation according to the method described in Example 1-4.
  • Examples 1-316 and 1-317 were obtained by using 1-(2-aminoethyl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-17 to perform alkylation, deprotection for the protective group, and lactamation cyclization according to the method described in Example 1-36.
  • Example 1-318 was obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform reductive alkylation according to the method described in Example 1-12, or Example 1-27.
  • Example 1-319 The compound of Example 1-319 was obtained by using 1-(piperidin-4-yl)-3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-194 to perform esterification according to the method described in Example 1-24.
  • Example 1-320 was obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 1-1, Step D to perform esterification according to the method described in Example 1-37.
  • the reaction mixture was added with ethyl acetate (250 ml), the precipitates were separated by filtration, and then the organic layer was separated, and dried over anhydrous magnesium sulfate.
  • the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound (24 g).
  • Example 1-322 The compound of Example 1-322 was obtained according to the method described in Example 1-321.
  • Example 1-323 The compound of Example 1-323 can be prepared by Method A or Method B mentioned below.
  • the compounds of Examples 1-332 to 1-650 were obtained by using 6-chloro-1-(piperidin-3-yl)-2,3-dihydro-1H-1,5-diazaphenalene obtained in Example 1-321, or 6-hydroxy-1-(piperidin-3-yl)-2,3-dihydro-1H-1,5-diazaphenalene obtained in Example 1-323 according to the methods described in Example 1-2 to 1-320.
  • Example 1-651 4-Chloro-1-(piperidin-3-yl)-2,3-dihydro-1H-1,5-diazaphenalene
  • Example 1-652 The compound of Example 1-652 was obtained according to the method described in Example 1-651.
  • Example 1-653 The compound of Example 1-653 was obtained according to Method A or Method B of Example 1-323,.
  • Example 1-654 to 1-661 were obtained by using 3-(4-chloro-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester according to the methods described in Examples 1-324 to 1-331.
  • Example 1-662 The compound of Example 1-662 was obtained according to the method described in Example 1-663 mentioned below.
  • Examples 1-664 to 1-672 were obtained by using 3-(7-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 1-663, Step A according to the methods described in Examples 1-323 to 1-331.
  • Example 1-673 The compound of Example 1-673 was obtained according to the method described in Example 1-674 mentioned below.
  • Examples 1-675 to 1-683 were obtained by using 3-(8-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 1-663, Step A according to the methods described in Examples 1-323 to 1-331.
  • Examples 1-684 and 1-685 were obtained from the compound of Example 1-691 mentioned below by referring to a known diazotization-Sandmeyer reaction (for example, Denny, William., et al., J. Med. Chem., 2002, 740 ; Kulka, J. Am. Chem. Soc., 75, 3597 (1953 ) and the like).
  • Examples 1-686 to 1-690 were obtained by using 3-(9-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 1-685 according to the methods described in Example 1-323 to 1-327.
  • Examples 1-692 to 1-694 were obtained by using 3-(9-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 1-685 according to the methods described in Example 1-329 to 1-331.
  • Examples 2-2 to 2-320 were obtained by using 4-(2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine obtained in Example 2-1 according to the methods described in Example 1-2 to 1-320.
  • Example 2-322 The compound of Example 2-322 was obtained in the same manner as that used for the compound of Example 1-322.
  • Example 2-323 The compound of Example 2-323 was obtained in the same manner as that used for the compound of Example 1-323.
  • Examples 2-324 to 2-331 were obtained by using 4-(6-chloro-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 24) obtained in Example 2-321, Step A according to the methods described in Example 1-324 to 1-331.
  • the compounds of Examples 2-332 to 2-650 were obtained by using 6-chloro-1-(piperidin-4-yl)-2,3-dihydro-1H-1,5-diazaphenalene obtained in Example 2-321, or 6-hydroxy-1-(piperidin-4-yl)-2,3-dihydro-1H-1,5-diazaphenalene obtained in Example 2-323 according to the methods described in Example 1-2 to 1-320.
  • Example 2-652 The compound of Example 2-652 was obtained according to the method described in Example 2-651.
  • Example 2-653 was obtained according to Method A or Method B of Example 1-323,.
  • Examples 2-654 to 2-661 were obtained by using 4-(4-chloro-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester according to the methods described in Example 1-324 to 1-331.
  • Example 2-662 The compound of Example 2-662 was obtained according to the method described in Example 2-663 mentioned below.
  • Examples 2-664 to 2-672 were obtained by using 4-(7-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 2-663, Step A according to the methods described in Examples 1-323 to 1-331.
  • Example 2-673 The compound of Example 2-673 was obtained according to the method described in Example 2-674 mentioned below.
  • Examples 2-675 to 2-683 were obtained by using 4-(8-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 2-663, Step A according to the methods described in Examples 1-323 to 1-331.
  • Examples 2-684 and 2-685 were obtained from the compound of Example 2-691 mentioned below by referring to a known diazotization-Sandmeyer reaction (for example, Denny, William , et al, J. Med. Chem., 2002, 740 ; Kulka, J. Am. Chem. Soc., 75, 3597 (1953 ) and the like).
  • Examples 2-686 to 2-690 were obtained by using 4-(9-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 2-685 according to the methods described in Example 1-323 to 1-327.
  • Examples 2-692 to 2-694 were obtained by using 4-(9-bromo-2,3-dihydro-1,5-diazaphenalen-1-yl)piperidine-1-carboxylic acid tert-butyl ester obtained in Example 2-685 according to the methods described in Example 1-329 to 1-331.
  • Examples 3-2 to 3-320 were obtained by using 3-(2,3-dihydro-1,5-diazaphenalen-1-yl)pyrrolidine obtained in Example 3-1 according to the methods described in Example 1-2 to 1-320.
  • Example 3-322 was obtained in the same manner as that used for the compound of Example 1-322.

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